|
Effective concentration of compound against HIV-1 LAI strain in CEM-SS cells
|
Homo sapiens
|
127.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bicyclam-GalCer analogue conjugates: synthesis and in vitro anti-HIV activity.
Year : 2004
Volume : 14
Issue : 2
First Page : 495
Last Page : 498
Authors : Daoudi JM, Greiner J, Aubertin AM, Vierling P.
Abstract : The synthesis of bipharmacophore anti-HIV compounds which, in a single molecule, combine two ligands, that is, the bicyclam AMD3100 and a GalCer analogue, that might inhibit several steps of the complex virus/cell cascade interactions has been performed. The 'double-drug' Gal-AMD3100 conjugates elicited inhibitory effects on T (or X4)-tropic HIV-1 replication in all CXCR4 expressing cell lines with EC(50) values ranging from 0.25 to 6.0 microM which were however approximately 40- to 125-fold lower than that of AMD3100. Concerning the mechanism of inhibition of the Gal-AMD3100 conjugates, experiments performed with X4 or R5HIV-1 strains and GHOST cells genetically modified to express CD4 and CXCR4 or CCR5 indicated clearly that the conjugates interact with CXCR4 and not with CCR5.
|
Inhibitory concentration of compound against HIV-1 LAI strain in GHOST CXCR4 cell line
|
Homo sapiens
|
0.95
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bicyclam-GalCer analogue conjugates: synthesis and in vitro anti-HIV activity.
Year : 2004
Volume : 14
Issue : 2
First Page : 495
Last Page : 498
Authors : Daoudi JM, Greiner J, Aubertin AM, Vierling P.
Abstract : The synthesis of bipharmacophore anti-HIV compounds which, in a single molecule, combine two ligands, that is, the bicyclam AMD3100 and a GalCer analogue, that might inhibit several steps of the complex virus/cell cascade interactions has been performed. The 'double-drug' Gal-AMD3100 conjugates elicited inhibitory effects on T (or X4)-tropic HIV-1 replication in all CXCR4 expressing cell lines with EC(50) values ranging from 0.25 to 6.0 microM which were however approximately 40- to 125-fold lower than that of AMD3100. Concerning the mechanism of inhibition of the Gal-AMD3100 conjugates, experiments performed with X4 or R5HIV-1 strains and GHOST cells genetically modified to express CD4 and CXCR4 or CCR5 indicated clearly that the conjugates interact with CXCR4 and not with CCR5.
|
Effective concentration against HIV-1(IIIB) replication in MT-4 cells
|
Human immunodeficiency virus 1
|
4.2
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams.
Year : 1996
Volume : 39
Issue : 1
First Page : 109
Last Page : 119
Authors : Bridger GJ, Skerlj RT, Padmanabhan S, Martellucci SA, Henson GW, Abrams MJ, Joao HC, Witvrouw M, De Vreese K, Pauwels R, De Clercq E.
Abstract : A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.
|
Effective concentration against HIV-2(ROD) replication in MT-4 cells
|
Human immunodeficiency virus 2
|
5.9
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams.
Year : 1996
Volume : 39
Issue : 1
First Page : 109
Last Page : 119
Authors : Bridger GJ, Skerlj RT, Padmanabhan S, Martellucci SA, Henson GW, Abrams MJ, Joao HC, Witvrouw M, De Vreese K, Pauwels R, De Clercq E.
Abstract : A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.
|
Effective concentration of compound against HIV-1 IIIB strain in MT-4 cells
|
Homo sapiens
|
65.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bicyclam-GalCer analogue conjugates: synthesis and in vitro anti-HIV activity.
Year : 2004
Volume : 14
Issue : 2
First Page : 495
Last Page : 498
Authors : Daoudi JM, Greiner J, Aubertin AM, Vierling P.
Abstract : The synthesis of bipharmacophore anti-HIV compounds which, in a single molecule, combine two ligands, that is, the bicyclam AMD3100 and a GalCer analogue, that might inhibit several steps of the complex virus/cell cascade interactions has been performed. The 'double-drug' Gal-AMD3100 conjugates elicited inhibitory effects on T (or X4)-tropic HIV-1 replication in all CXCR4 expressing cell lines with EC(50) values ranging from 0.25 to 6.0 microM which were however approximately 40- to 125-fold lower than that of AMD3100. Concerning the mechanism of inhibition of the Gal-AMD3100 conjugates, experiments performed with X4 or R5HIV-1 strains and GHOST cells genetically modified to express CD4 and CXCR4 or CCR5 indicated clearly that the conjugates interact with CXCR4 and not with CCR5.
|
Effective concentration of compound against HIV-1 89.6 strain in PBMC cells
|
Homo sapiens
|
3.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New bicyclam-GalCer analogue conjugates: synthesis and in vitro anti-HIV activity.
Year : 2004
Volume : 14
Issue : 2
First Page : 495
Last Page : 498
Authors : Daoudi JM, Greiner J, Aubertin AM, Vierling P.
Abstract : The synthesis of bipharmacophore anti-HIV compounds which, in a single molecule, combine two ligands, that is, the bicyclam AMD3100 and a GalCer analogue, that might inhibit several steps of the complex virus/cell cascade interactions has been performed. The 'double-drug' Gal-AMD3100 conjugates elicited inhibitory effects on T (or X4)-tropic HIV-1 replication in all CXCR4 expressing cell lines with EC(50) values ranging from 0.25 to 6.0 microM which were however approximately 40- to 125-fold lower than that of AMD3100. Concerning the mechanism of inhibition of the Gal-AMD3100 conjugates, experiments performed with X4 or R5HIV-1 strains and GHOST cells genetically modified to express CD4 and CXCR4 or CCR5 indicated clearly that the conjugates interact with CXCR4 and not with CCR5.
|
Antiviral activity against HIV1 LAV in PBMC
|
Human immunodeficiency virus 1
|
470.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-HIV properties of new hydroxyquinoline-polyamine conjugates on cells infected by HIV-1 LAV and HIV-1 BaL viral strains.
Year : 2006
Volume : 16
Issue : 23
First Page : 5988
Last Page : 5992
Authors : Moret V, Dereudre-Bosquet N, Clayette P, Laras Y, Pietrancosta N, Rolland A, Weck C, Marc S, Kraus JL.
Abstract : To find new derivatives that block different virus strains entry in cells bearing specific surface receptors represent an interesting challenge for medicinal chemists. Here, we report the synthesis and the anti-HIV properties of a new series of analogues based on the introduction of quinoline moiety on various polyamine backbones, including polyazamacrocycles. Three compounds 7, 8, and 10 of this series were found active on PBMCs cells infected by HIV-1 LAV or by HIV-1 BaL, in contrast the well-known reference compound 1a (AMD 3100) was found only active on HIV-1 LAV strain.
|
Displacement of [125I]12G5 antibody from human wild type CXCR4 expressed in COS7 cells
|
Homo sapiens
|
890.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Displacement of [125I]12G5 antibody from transmembrane domain 5 of human CXCR4 Q200A mutant expressed in COS7 cells
|
Homo sapiens
|
560.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Displacement of [125I]12G5 antibody from transmembrane domain 7 of human CXCR4 H281A mutant expressed in COS7 cells
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human wild type CXCR4 expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
220.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 H113A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
740.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 L120F mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
330.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 F172A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
170.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 V196A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 Q200W mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
400.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 Q200A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
930.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 H203A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 Y255A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
660.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at transmembrane domain 6 of human CXCR4 I259A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 I259W mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
630.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 H281A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
190.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antagonist activity at human CXCR4 T287A mutant expressed in COS7 cells coexpressing G protein Gqi4myr assessed as inhibition of CXCL12-induced phosphatidylinositol turnover
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NL43 infected in U87.CD4 cells expressing human wild type CXCR4
|
Human immunodeficiency virus 1
|
14.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NDK infected in U87.CD4 cells expressing human wild type CXCR4
|
Human immunodeficiency virus 1
|
7.6
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 clinical isolate 10 infected in U87.CD4 cells expressing human wild type CXCR4
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NL43 infected in U87.CD4 cells expressing human CXCR4 D171N mutant
|
Human immunodeficiency virus 1
|
46.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NDK infected in U87.CD4 cells expressing human CXCR4 D171N mutant
|
Human immunodeficiency virus 1
|
17.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 clinical isolate 10 infected in U87.CD4 cells expressing human CXCR4 D171N mutant
|
Human immunodeficiency virus 1
|
19.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NL43 infected in U87.CD4 cells expressing human CXCR4 D262N mutant
|
Human immunodeficiency virus 1
|
600.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NL43 infected in U87.CD4 cells expressing human CXCR4 H281A mutant
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 NDK infected in U87.CD4 cells expressing human CXCR4 H281A mutant
|
Human immunodeficiency virus 1
|
1.9
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 clinical isolate 10 infected in U87.CD4 cells expressing human CXCR4 H281A mutant
|
Human immunodeficiency virus 1
|
2.4
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Antiviral activity against HIV1 clinical isolate 10 infected U87.CD4 cells expressing human CXCR4 E288A mutant
|
Human immunodeficiency virus 1
|
121.0
nM
|
|
Journal : J. Biol. Chem.
Title : Molecular mechanism of action of monocyclam versus bicyclam non-peptide antagonists in the CXCR4 chemokine receptor.
Year : 2007
Volume : 282
Issue : 37
First Page : 27354
Last Page : 27365
Authors : Rosenkilde MM, Gerlach LO, Hatse S, Skerlj RT, Schols D, Bridger GJ, Schwartz TW.
Abstract : AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
|
Displacement of [125I]SDF1alpha from CXCR4 expressed in CHOK1 cells
|
None
|
0.81
nM
|
|
Displacement of [125I]SDF1alpha from CXCR4 expressed in CHOK1 cells
|
None
|
100.0
%
|
|
Journal : J. Biol. Chem.
Title : Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers.
Year : 2007
Volume : 282
Issue : 41
First Page : 30062
Last Page : 30069
Authors : Sohy D, Parmentier M, Springael JY.
Abstract : Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross-inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents.
|
Displacement of [125I]MCP1 from CCR2/CXCR4 expressed in CHOK1 cells
|
None
|
0.09
nM
|
|
Displacement of [125I]MCP1 from CCR2/CXCR4 expressed in CHOK1 cells
|
None
|
36.2
%
|
|
Journal : J. Biol. Chem.
Title : Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers.
Year : 2007
Volume : 282
Issue : 41
First Page : 30062
Last Page : 30069
Authors : Sohy D, Parmentier M, Springael JY.
Abstract : Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross-inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents.
|
Displacement of [125I]SDF1alpha from CCR2/CXCR4 expressed in CHOK1 cells
|
None
|
0.04
nM
|
|
Displacement of [125I]SDF1alpha from CCR2/CXCR4 expressed in CHOK1 cells
|
None
|
87.1
%
|
|
Journal : J. Biol. Chem.
Title : Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers.
Year : 2007
Volume : 282
Issue : 41
First Page : 30062
Last Page : 30069
Authors : Sohy D, Parmentier M, Springael JY.
Abstract : Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross-inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents.
|
Antagonist activity at CXCR4 in human Jurkat cells assessed as inhibition of SDF1-induced cell migration
|
Homo sapiens
|
27.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 64Cu-AMD3100--a novel imaging agent for targeting chemokine receptor CXCR4.
Year : 2009
Volume : 17
Issue : 4
First Page : 1486
Last Page : 1493
Authors : Jacobson O, Weiss ID, Szajek L, Farber JM, Kiesewetter DO.
Abstract : CXCR4 is a chemokine receptor which has been shown to be exploited by various tumors for increased survival, invasion, and homing to target organs. We developed a one step radiosynthesis for labeling the CXCR4-specific antagonist AMD3100 with Cu-64 to produce (64)Cu-AMD3100 with a specific activity of 11.28Ci/ micromol (417GBq/ micromol) at the end of radiosynthesis. Incorporation of Cu(II) ion into AMD3100 did not change its ability to inhibit cellular migration in response to the (only) CXCR4 ligand, SDF-1/CXCL12. (64)Cu-AMD3100 binding affinity to CXCR4 was found to be 62.7 microM. Biodistribution of (64)Cu-AMD3100 showed accumulation in CXCR4-expressing organs and tissues, a renal clearance pathway, and an anomalous specific accumulation in the liver. We conclude that (64)Cu-AMD3100 exhibits promise as a potential PET imaging agent for visualization of CXCR4-positive tumors and metastases and might be used to guide and monitor anti-CXCR4 tumor therapy.
|
Antiviral activity against HIV1 NL4.3 in human MT4 cells
|
Human immunodeficiency virus 1
|
0.0015
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects.
Year : 2007
Volume : 51
Issue : 7
First Page : 2351
Last Page : 2358
Authors : Stone ND, Dunaway SB, Flexner C, Tierney C, Calandra GB, Becker S, Cao YJ, Wiggins IP, Conley J, MacFarland RT, Park JG, Lalama C, Snyder S, Kallungal B, Klingman KL, Hendrix CW.
Abstract : AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.
|
Displacement of [125I]CXCL12 from CXCR4 in human CEM cells
|
Homo sapiens
|
245.0
nM
|
|
Journal : J. Med. Chem.
Title : Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo.
Year : 2008
Volume : 51
Issue : 24
First Page : 7915
Last Page : 7920
Authors : Thoma G, Streiff MB, Kovarik J, Glickman F, Wagner T, Beerli C, Zerwes HG.
Abstract : The interaction of the chemokine receptor CXCR4 with its ligand CXCL12 is involved in many biological processes such as hematopoesis, migration of immune cells, as well as in cancer metastasis. CXCR4 also mediates the infection of T-cells with X4-tropic HIV functioning as a coreceptor for the viral envelope protein gp120. Here, we describe highly potent, selective CXCR4 inhibitors that block CXCR4/CXCL12 interactions in vitro and in vivo as well as the infection of target cells by X4-tropic HIV.
|
Displacement of [125I]CXCL12 from CXCR4 in rat IR983F cells
|
Rattus norvegicus
|
108.0
nM
|
|
Journal : J. Med. Chem.
Title : Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo.
Year : 2008
Volume : 51
Issue : 24
First Page : 7915
Last Page : 7920
Authors : Thoma G, Streiff MB, Kovarik J, Glickman F, Wagner T, Beerli C, Zerwes HG.
Abstract : The interaction of the chemokine receptor CXCR4 with its ligand CXCL12 is involved in many biological processes such as hematopoesis, migration of immune cells, as well as in cancer metastasis. CXCR4 also mediates the infection of T-cells with X4-tropic HIV functioning as a coreceptor for the viral envelope protein gp120. Here, we describe highly potent, selective CXCR4 inhibitors that block CXCR4/CXCL12 interactions in vitro and in vivo as well as the infection of target cells by X4-tropic HIV.
|
Antiviral activity against X4-tropic HIV1 3B assessed as inhibition of viral attachment
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : J. Med. Chem.
Title : Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo.
Year : 2008
Volume : 51
Issue : 24
First Page : 7915
Last Page : 7920
Authors : Thoma G, Streiff MB, Kovarik J, Glickman F, Wagner T, Beerli C, Zerwes HG.
Abstract : The interaction of the chemokine receptor CXCR4 with its ligand CXCL12 is involved in many biological processes such as hematopoesis, migration of immune cells, as well as in cancer metastasis. CXCR4 also mediates the infection of T-cells with X4-tropic HIV functioning as a coreceptor for the viral envelope protein gp120. Here, we describe highly potent, selective CXCR4 inhibitors that block CXCR4/CXCL12 interactions in vitro and in vivo as well as the infection of target cells by X4-tropic HIV.
|
Antiviral activity against HIV1 3B in human MT4 cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
410.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Bis-14-membered ring diketal diamines: synthesis and evaluation of their anti-HIV and anti-tumoral activities.
Year : 2009
Volume : 44
Issue : 8
First Page : 3138
Last Page : 3146
Authors : Affani R, Pélissier F, Aubertin AM, Dugat D.
Abstract : Chiral and achiral macrocyclic bis-diketal diamines, analogs of bicyclam AMD 3100, were synthesized in three steps from the previously obtained 14-membered ring diketal dilactams. Their monoreduction with lithium aluminium hydride gave the corresponding diketal aminolactams. Coupling these with dibromo-p-xylene led to xylyl dimer compounds. A second reduction step yielded the expected bis-diketal diamines in the methyl and unsubstituted series. Biological tests on the unreduced and reduced dimers showed both weak anti-HIV and anti-proliferative activities for the bis-diphenyl diketal aminolactam 13b, with a mode of action probably different from that of AMD 3100.
|
Antiviral activity against HIV1 LAI in human CEM-SS cells assessed as inhibition of viral replication
|
Human immunodeficiency virus 1
|
320.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Bis-14-membered ring diketal diamines: synthesis and evaluation of their anti-HIV and anti-tumoral activities.
Year : 2009
Volume : 44
Issue : 8
First Page : 3138
Last Page : 3146
Authors : Affani R, Pélissier F, Aubertin AM, Dugat D.
Abstract : Chiral and achiral macrocyclic bis-diketal diamines, analogs of bicyclam AMD 3100, were synthesized in three steps from the previously obtained 14-membered ring diketal dilactams. Their monoreduction with lithium aluminium hydride gave the corresponding diketal aminolactams. Coupling these with dibromo-p-xylene led to xylyl dimer compounds. A second reduction step yielded the expected bis-diketal diamines in the methyl and unsubstituted series. Biological tests on the unreduced and reduced dimers showed both weak anti-HIV and anti-proliferative activities for the bis-diphenyl diketal aminolactam 13b, with a mode of action probably different from that of AMD 3100.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as inhibition of virus replication after 4 days by MTT assay
|
Human immunodeficiency virus 1
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication.
Year : 2010
Volume : 53
Issue : 3
First Page : 1250
Last Page : 1260
Authors : Bridger GJ, Skerlj RT, Hernandez-Abad PE, Bogucki DE, Wang Z, Zhou Y, Nan S, Boehringer EM, Wilson T, Crawford J, Metz M, Hatse S, Princen K, De Clercq E, Schols D.
Abstract : Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.
|
Antiviral activity against HIV1 NL4.3 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
3.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 BZ167 in human PBMC assessed as p24 antigen level by ELISA
|
Human immunodeficiency virus 1
|
18.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity.
Year : 2010
Volume : 54
Issue : 1
First Page : 134
Last Page : 142
Authors : Huet T, Kerbarh O, Schols D, Clayette P, Gauchet C, Dubreucq G, Vincent L, Bompais H, Mazinghien R, Querolle O, Salvador A, Lemoine J, Lucidi B, Balzarini J, Petitou M.
Abstract : Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
|
Antiviral activity against HIV1 JRCSF infected in human vaginal intraepithelial cells assessed as decrease in viral genomic integration at 1 uM by singleplex PCR assay
|
Human immunodeficiency virus type 1 (JRCSF ISOLATE)
|
177.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Ex vivo comparison of microbicide efficacies for preventing HIV-1 genomic integration in intraepithelial vaginal cells.
Year : 2010
Volume : 54
Issue : 2
First Page : 763
Last Page : 772
Authors : McElrath MJ, Ballweber L, Terker A, Kreger A, Sakchalathorn P, Robinson B, Fialkow M, Lentz G, Hladik F.
Abstract : Vaginally applied microbicides hold promise as a strategy to prevent sexual HIV transmission. Several nonspecific microbicides, including the polyanion cellulose sulfate, have been evaluated in large-scale clinical trials but have failed to show significant efficacy. These findings have prompted a renewed search for preclinical testing systems that can predict negative outcomes of microbicide trials. Moreover, the pipeline of potential topical microbicides has been expanded to include antiretroviral agents, such as reverse transcriptase, fusion, and integrase inhibitors. Using a novel ex vivo model of vaginal HIV-1 infection, we compared the prophylactic potentials of two forms of the fusion inhibitor T-20, the CCR5 antagonist TAK-778, the integrase inhibitor 118-D-24, and cellulose sulfate (Ushercell). The T-20 peptide with free N- and C-terminal amino acids was the most efficacious compound, causing significantly greater inhibition of viral genomic integration in intraepithelial vaginal leukocytes, measured by an optimized real-time PCR assay, than the more water-soluble N-acetylated T-20 peptide (Fuzeon) (50% inhibitory concentration [IC50], 0.153 microM versus 51.2 microM [0.687 ng/ml versus 230 ng/ml]; P<0.0001). In contrast, no significant difference in IC50s was noted in peripheral blood cells (IC50, 13.58 microM versus 7.57 microM [61 ng/ml versus 34 ng/ml]; P=0.0614). Cellulose sulfate was the least effective of all the compounds tested (IC50, 1.8 microg/ml). These results highlight the merit of our model for screening the mucosal efficacies of novel microbicides and their formulations and potentially rank ordering candidates for clinical evaluation.
|
Antiviral activity against HIV 1 3B infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
34.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 3B harboring integrase E92Q S230N double mutant infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay selected after 20 passages in presence of compound
|
Human immunodeficiency virus 1
|
49.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 3B harboring integrase L34M mutant infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay selected after 40 passages in presence of compound
|
Human immunodeficiency virus 1
|
28.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 3B harboring integrase E92Q, S230N and L34M triple mutant infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay selected after 60 passages in presence of compound
|
Human immunodeficiency virus 1
|
56.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay
|
Human immunodeficiency virus 1
|
14.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay after 20 passages selected in presence of compound
|
Human immunodeficiency virus 1
|
8.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay after 40 passages selected in presence of compound
|
Human immunodeficiency virus 1
|
8.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV 1 RIN HIV 1 RIN harboring integrase gene infected in MT-4 cells assessed as inhibition of virus-induced cytopathic effect by MTT assay after 60 passages selected in presence of compound
|
Human immunodeficiency virus 1
|
8.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutations in human immunodeficiency virus type 1 integrase confer resistance to the naphthyridine L-870,810 and cross-resistance to the clinical trial drug GS-9137.
Year : 2008
Volume : 52
Issue : 6
First Page : 2069
Last Page : 2078
Authors : Hombrouck A, Voet A, Van Remoortel B, Desadeleer C, De Maeyer M, Debyser Z, Witvrouw M.
Abstract : To gain further insight into the understanding of the antiviral resistance patterns and mechanisms of the integrase strand transfer inhibitor L-870,810, the prototypical naphthyridine analogue, we passaged the human immunodeficiency virus type 1 strain HIV-1(III(B)) in cell culture in the presence of increasing concentrations of L-870,810 (III(B)/L-870,810). The mutations L74M, E92Q, and S230N were successively selected in the integrase. The L74M and E92Q mutations have both been associated in the past with resistance against the diketo acid (DKA) analogues L-708,906 and S-1360 and the clinical trial drugs MK-0518 and GS-9137. After 20, 40, and 60 passages in the presence of L-870,810, III(B)/L-870,810 displayed 22-, 34-, and 110-fold reduced susceptibility to L-870,810, respectively. Phenotypic cross-resistance against the DKA analogue CHI-1043 and MK-0518 was modest but that against GS-9137 was pronounced. Recombination of the mutant integrase genes into the wild-type background reproduced the resistance profile of the resistant III(B)/L-870,810 strains. In addition, resistance against L-870,810 was accompanied by reduced viral replication kinetics and reduced enzymatic activity of integrase. In conclusion, the accumulation of L74M, E92Q, and S230N mutations in the integrase causes resistance to the naphthyridine L-870,810 and cross-resistance to GS-9137. These data may have implications for cross-resistance of different integrase inhibitors in the clinic.
|
Antiviral activity against HIV1 NL4-3 infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus 1
|
41.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 X4 infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus 1
|
15.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 89.6 infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus 1
|
44.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 JRCSF infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus type 1 (JRCSF ISOLATE)
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 R5 infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus 1
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 A018H infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus 1
|
38.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 A018G infected in human PBMC assessed as inhibition of viral p24 antigen production after 7 to 10 days by ELISA
|
Human immunodeficiency virus 1
|
32.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 NL4-3 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
4.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against HIV1 HXB2 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
6.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against NRTI-resistant HIV1 HXB2 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
9.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against NNRTI-resistant HIV1 HXB2 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
7.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against PI-resistant HIV1 HXB2 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
9.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against multidrug resistant HIV1 HXB2 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
5.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Antiviral activity against T20-resistant HIV1 NL4-3 infected in HEK293 cells assessed as inhibition of viral replication after 2 days
|
Human immunodeficiency virus 1
|
2.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to wild type CXCR4 expressed in HEK293 cells
|
None
|
289.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 V99A mutant expressed in HEK293 cells
|
Homo sapiens
|
258.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 V112A mutant expressed in HEK293 cells
|
Homo sapiens
|
196.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 H113A mutant expressed in HEK293 cells
|
Homo sapiens
|
296.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 D181A mutant expressed in HEK293 cells
|
Homo sapiens
|
143.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 H203A mutant expressed in HEK293 cells
|
Homo sapiens
|
259.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 E275A mutant expressed in HEK293 cells
|
Homo sapiens
|
235.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 E277A mutant expressed in HEK293 cells
|
Homo sapiens
|
469.5
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 V280A mutant expressed in HEK293 cells
|
Homo sapiens
|
175.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 H281A mutant expressed in HEK293 cells
|
Homo sapiens
|
72.7
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 W283A mutant expressed in HEK293 cells
|
Homo sapiens
|
300.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Inhibition of Mab 12G5 binding to CXCR4 I284A mutant expressed in HEK293 cells
|
Homo sapiens
|
265.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Year : 2009
Volume : 53
Issue : 7
First Page : 2940
Last Page : 2948
Authors : Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N.
Abstract : The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
|
Binding affinity to CXCR4
|
None
|
74.0
nM
|
|
Journal : J. Med. Chem.
Title : Chemokine receptor antagonists.
Year : 2012
Volume : 55
Issue : 22
First Page : 9363
Last Page : 9392
Authors : Pease J, Horuk R.
|
Inhibition of anti-CXCR4 mAbs clone 1D9 binding to CXCR4 in human SUPT1 cells incubated for 15 mins by FACS
|
Homo sapiens
|
1.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Inhibition of anti-CXCR4 mAbs clone 12G5 binding to CXCR4 in human SUPT1 cells incubated for 15 mins by FACS
|
Homo sapiens
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Inhibition of anti-CXCR4 mAbs clone 173 binding to CXCR4 in human SUPT1 cells incubated for 15 mins by FACS
|
Homo sapiens
|
0.02
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Antiviral activity against X4 HIV1 NL4.3 infected in human PBMC assessed as inhibition of viral replication pre-incubated for 30 mins measured 5 days post infection by MTT assay
|
Human immunodeficiency virus 1
|
0.002
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Antiviral activity against X4 HIV1 NL4.3 infected in human MT4 cells assessed as inhibition of viral replication pre-incubated for 30 mins measured 5 days post infection by MTT assay
|
Human immunodeficiency virus 1
|
0.017
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Antagonist activity against CXCR4 expressed in U87.CD.CXCR4 cells assessed as inhibition of CXCL12-induced calcium signaling incubated for 10 mins by FLIPR
|
Homo sapiens
|
0.17
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Inhibition of CXCL-12'AF647 binding to CXCR4 in human SUPT1 cells incubated for 15 mins by FACS
|
Homo sapiens
|
0.057
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : HIV-1 X4 activities of polycationic "viologen" based dendrimers by interaction with the chemokine receptor CXCR4: study of structure-activity relationship.
Year : 2012
Volume : 55
Issue : 23
First Page : 10405
Last Page : 10413
Authors : Asaftei S, Huskens D, Schols D.
Abstract : A series of "viologen" based dendrimers with polycationic scaffold carrying 10, 18, 26, 42, and 90 charges per molecule were used to determine the structure-activity relationship (SAR) with regard to HIV-1 inhibitory activity. The studies involved five compounds with a high activity against HIV-1 already utilized in our previous study (1) and five new dendrimers. Such dendrimers block HIV-1 entry into the cell, indicating that they bind to HIV-1 surface proteins and/or on the host cell receptors required for entry. The increasing positive character of dendrimers leads to more cytotoxicity. The 10 charges dendrimers (1, 6) have less influence on the cell viability but low inhibition of the binding of the CXCR4 mAb clone 1D9. Thus, dendrimers with 18 charges (2, 7) are the most promising CXCR4 imaging probes. We report the design, synthesis, and biological activity of new HIV-1 inhibitors that are conceptually distinct from those of the existing HIV-1 inhibitors.
|
Antiviral activity against T-cell line-tropic HIV1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
32.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins.
Year : 2015
Volume : 23
Issue : 15
First Page : 4423
Last Page : 4427
Authors : Mizuguchi T, Ohashi N, Nomura W, Komoriya M, Hashimoto C, Yamamoto N, Murakami T, Tamamura H.
Abstract : Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.
|
Antiviral activity against T-cell line-tropic HIV1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 5 days by MTT assay in presence of 2.5 uM of chloroquine
|
Human immunodeficiency virus 1
|
39.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins.
Year : 2015
Volume : 23
Issue : 15
First Page : 4423
Last Page : 4427
Authors : Mizuguchi T, Ohashi N, Nomura W, Komoriya M, Hashimoto C, Yamamoto N, Murakami T, Tamamura H.
Abstract : Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.
|
Antiviral activity against T-cell line-tropic HIV1 NL4-3 infected in human MT4 cells assessed as inhibition of virus-induced cytopathogenicity after 5 days by MTT assay in presence of 5 uM of chloroquine
|
Human immunodeficiency virus 1
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins.
Year : 2015
Volume : 23
Issue : 15
First Page : 4423
Last Page : 4427
Authors : Mizuguchi T, Ohashi N, Nomura W, Komoriya M, Hashimoto C, Yamamoto N, Murakami T, Tamamura H.
Abstract : Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.
|
Antiviral activity against HIV1 3B infected in human MT4 cells assessed as reduction in virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
2.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities.
Year : 2016
Volume : 114
First Page : 65
Last Page : 78
Authors : Zhang H, Kang D, Huang B, Liu N, Zhao F, Zhan P, Liu X.
Abstract : CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced.
|
Antiviral activity against HIV2 ROD infected in human MT4 cells assessed as reduction in virus-induced cytopathic effect after 5 days by MTT assay
|
Human immunodeficiency virus type 2 (ISOLATE ROD)
|
2.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities.
Year : 2016
Volume : 114
First Page : 65
Last Page : 78
Authors : Zhang H, Kang D, Huang B, Liu N, Zhao F, Zhan P, Liu X.
Abstract : CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced.
|
Inhibition of CXCL2alpha-induced invasion of human MDA-MB-231 cells at 100 nM after 22 hrs by hematoxylin/eosin-staining based matrigel assay
|
Homo sapiens
|
62.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Symmetrical bis-tertiary amines as novel CXCR4 inhibitors.
Year : 2016
Volume : 118
First Page : 340
Last Page : 350
Authors : Bai R, Liang Z, Yoon Y, Liu S, Gaines T, Oum Y, Shi Q, Mooring SR, Shim H.
Abstract : CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure-activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency.
|
Inhibition of PE-conjugated-12G5 anti-CXCR4 antibody binding to CXCR4 in human CEM-CCRF cells preincubated for 30 mins followed by antibody addition by FACS Canto II cytofluorometric analysis
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Exploring the N-Terminal Region of C-X-C Motif Chemokine 12 (CXCL12): Identification of Plasma-Stable Cyclic Peptides As Novel, Potent C-X-C Chemokine Receptor Type 4 (CXCR4) Antagonists.
Year : 2016
Volume : 59
Issue : 18
First Page : 8369
Last Page : 8380
Authors : Di Maro S, Trotta AM, Brancaccio D, Di Leva FS, La Pietra V, Ieranò C, Napolitano M, Portella L, D'Alterio C, Siciliano RA, Sementa D, Tomassi S, Carotenuto A, Novellino E, Scala S, Marinelli L.
Abstract : We previously reported the discovery of a CXCL12-mimetic cyclic peptide (2) as a selective CXCR4 antagonist showing promising in vitro and in vivo anticancer activity. However, further development of this peptide was hampered by its degradation in biological fluids as well as by its low micromolar affinity for the receptor. Herein, extensive chemical modifications led to the development of a new analogue (10) with enhanced potency, specificity, and plasma stability. A combined approach of Ala-amino acid scan, NMR, and molecular modeling unraveled the reasons behind the improved binding properties of 10 vs 2. Biological investigations on leukemia (CEM) and colon (HT29 and HCT116) cancer cell lines showed that 10 is able to impair CXCL12-mediated cell migration, ERK-phosphorylation, and CXCR4 internalization. These outcomes might pave the way for the future preclinical development of 10 in CXCR4 overexpressing leukemia and colon cancer.
|
Competitive Binding Assay: A synthetic 14-mer peptide, TN14003, was previously reported to block both SDF-1/CXCR4 mediated invasion in vitro and metastasis in vivo with a high specificity by binding competitively with its ligand SDF-1. Aa competitive binding assay using biotin-labeled TN14003 and streptavidin-conjugated rhodamine was developed to determine the binding efficiency of new chemical entities to the SDF-1 binding domain of CXCR4. Cells incubated with high affinity compounds show only blue nuclear staining, whereas compounds with low affinity result in staining CXCR4 (red; rhodamine) as well as the nuclei (blue; cytox blue).
|
None
|
100.0
nM
|
|
Title : Tricyclic amino containing compounds for treatment or prevention of symptoms associated with endocrine dysfunction
Year : 2015
|
Inhibition of CXCR4/CXCL12 interaction-mediated chemotaxis in human MDA-MB-231 cells assessed as inhibition of cell invasion at 100 nM after 22 hrs by hematoxylin/eosin dye-based matrigel assay relative to control
|
Homo sapiens
|
55.0
%
|
|
Journal : Eur J Med Chem
Title : Development of CXCR4 modulators by virtual HTS of a novel amide-sulfamide compound library.
Year : 2017
Volume : 126
First Page : 464
Last Page : 475
Authors : Bai R, Shi Q, Liang Z, Yoon Y, Han Y, Feng A, Liu S, Oum Y, Yun CC, Shim H.
Abstract : CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and the amide-sulfamide pharmacophore was a novel and effective framework blocking CXCR4 function.
|
Displacement of [125I]CXCL12 from human CXCR4 expressed in HEK293 cell membranes after 1.5 hrs by Topcount method
|
Homo sapiens
|
213.1
nM
|
|
Journal : J Med Chem
Title : Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond.
Year : 2018
Volume : 61
Issue : 3
First Page : 818
Last Page : 833
Authors : Wu CH, Song JS, Kuan HH, Wu SH, Chou MC, Jan JJ, Tsou LK, Ke YY, Chen CT, Yeh KC, Wang SY, Yeh TK, Tseng CT, Huang CL, Wu MH, Kuo PC, Lee CJ, Shia KS.
Abstract : The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16 into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor-ligand interactions for further structural modifications.
|
Antagonist activity at CXCR4 (unknown origin)
|
Homo sapiens
|
44.0
nM
|
|
Journal : Eur J Med Chem
Title : An update on small molecules targeting CXCR4 as starting points for the development of anti-cancer therapeutics.
Year : 2017
Volume : 139
First Page : 519
Last Page : 530
Authors : Grande F, Giancotti G, Ioele G, Occhiuzzi MA, Garofalo A.
Abstract : CXCR4 (C-X-C Chemokine Receptor type 4) and its natural ligand SDF-1α (Stromal-Derived-Factor-1α) are involved in a number of physiological and pathological processes including cancer spread and progression. Over the past few years, numerous CXCR4 antagonists have been identified and currently are in different development stages as potential agents for the treatment of several diseases involving the CXCR4/SDF-1α axis. Herein, we focus on small molecules reported in literature between 2013 and 2017, claimed as CXCR4 antagonists and potentially useful in the treatment of cancer and other diseases where this receptor is involved. Most of the compounds resulted from a chemical optimization of previously identified molecules and some of them could represent suitable candidates for the development of advanced anticancer agents.
|
Inhibition of CXCR4-mediated chemotaxis in human MDA-MB-231 cells assessed as inhibition of CXCL12alpha-induced cell invasion at 100 nM after 22 hrs by hematoxylin/eosin dye-based matrigel assay relative to control
|
Homo sapiens
|
55.0
%
|
|
Journal : Eur J Med Chem
Title : Novel anti-inflammatory agents targeting CXCR4: Design, synthesis, biological evaluation and preliminary pharmacokinetic study.
Year : 2017
Volume : 136
First Page : 360
Last Page : 371
Authors : Bai R, Liang Z, Yoon Y, Salgado E, Feng A, Gurbani S, Shim H.
Abstract : CXCR4 plays a crucial role in the inflammatory disease process, providing an attractive means for drug targeting. A series of novel amide-sulfamide derivatives were designed, synthesized and comprehensively evaluated. This new scaffold exhibited much more potent CXCR4 inhibitory activity, with more than 70% of the compounds showed notably better binding affinity than the reference drug AMD3100 in the binding assay. Additionally, in the Matrigel invasion assay, most of our compounds significantly blocked the tumor cell invasion, demonstrating superior efficacy compared to AMD3100. Furthermore, compound IIj blocked mice ear inflammation by 75% and attenuated ear edema and damage substantially in an in vivo model of inflammation. Western blot analyses revealed that CXCR4 modulator IIj significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, compound IIj had no observable cytotoxicity and displayed a favourable plasma stability in our preliminary pharmacokinetic study. The preliminary structure-activity relationships were also summarized. In short, this novel amide-sulfamide scaffold exhibited potent CXCR4 inhibitory activity both in vitro and in vivo. These results also confirmed that developing modulators targeting CXCR4 provides an exciting avenue for treatment of inflammation.
|
Anti-inflammatory activity in Balb/c mouse model of hypereosinophilia assessed as inhibition of eosinophil infiltration at 12.6 umol/kg, ip dosed 2 hrs before allergen challenge
|
Mus musculus
|
33.0
%
|
|
Journal : J Med Chem
Title : Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia.
Year : 2018
Volume : 61
Issue : 17
First Page : 7671
Last Page : 7686
Authors : Regenass P, Abboud D, Daubeuf F, Lehalle C, Gizzi P, Riché S, Hachet-Haas M, Rohmer F, Gasparik V, Boeglin D, Haiech J, Knehans T, Rognan D, Heissler D, Marsol C, Villa P, Galzi JL, Hibert M, Frossard N, Bonnet D.
Abstract : We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor. While both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo and to explore the activity of chemokine neutralization in inflammatory and related diseases.
|
Displacement of 12G5-CXCL12 from CXCR4 in human HPBALL cells after 3 hrs by FACS analysis
|
Homo sapiens
|
290.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and structure-activity-relationship of a novel series of CXCR4 antagonists.
Year : 2018
Volume : 149
First Page : 30
Last Page : 44
Authors : Li Z, Wang Y, Fu C, Wang X, Wang JJ, Zhang Y, Zhou D, Zhao Y, Luo L, Ma H, Lu W, Zheng J, Zhang X.
Abstract : The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC50 = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC50 = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists.
|
Antagonist activity at CXCR4 in human CD4+ T cells assessed as inhibition of CXCL12-mediated cytosolic calcium level preincubated with compounds followed by CXCL12 stimulation by calcium 4 dye-based FLIPR assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and structure-activity-relationship of a novel series of CXCR4 antagonists.
Year : 2018
Volume : 149
First Page : 30
Last Page : 44
Authors : Li Z, Wang Y, Fu C, Wang X, Wang JJ, Zhang Y, Zhou D, Zhao Y, Luo L, Ma H, Lu W, Zheng J, Zhang X.
Abstract : The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC50 = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC50 = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists.
|
Antiviral activity against HIV1 3B
|
Human immunodeficiency virus 1
|
3.0
nM
|
|
Journal : Eur J Med Chem
Title : The chemical diversity and structure-based evolution of non-peptide CXCR4 antagonists with diverse therapeutic potential.
Year : 2018
Volume : 149
First Page : 148
Last Page : 169
Authors : Peng D, Cao B, Zhou YJ, Long YQ.
Abstract : The CXC chemokine receptor 4 (CXCR4) is a highly reserved G-protein coupled 7-transmembrane (TM) chemokine receptor which consists of 352 amino acids. CXCR4 has only one endogenous chemokine ligand of CXCL12, besides several other natural nonchemokine ligands such as extracellular ubiquitin and noncognate ligand of MIF. CXCR4 strongly binds to CXCL12 and the resulting CXCLl2/CXCR4 axis is the molecular basis of their various biological functions, which include: (1) mediating immune and inflammatory response; (2) regulation of hematopoietic stem cell migration and homing; (3) an essential co-receptor for HIV entry into host cells; (4) participation in the process of embryonic development; (5) malignant tumor invasion and metastasis; (6) myocardial infarction, ischemic stroke and acute kidney injury. Correspondingly, CXCR4 antagonists find potential therapeutic applications in HIV infection, as well as hematopoietic stem cell migration, inflammation, immune-related diseases, tumor and ischemic diseases. Recently, great achievements have been made and a number of non-peptide CXCR4 antagonists with diversity scaffolds have been discovered. In this review, the discovery of small molecule CXCR4 antagonists focused on the structures, activities, evolution and development of representative CXCR4 antagonists is comprehensively described. The central role of CXCR4 in diverse cellular signaling pathways and its involvement in several diseases progressions are discussed as well.
|
Inhibition of CXCR4 in human MDA-MB-231 cells assessed as decrease in CXCL12-dependent cell invasion at 100 nM after 22 hrs by hematoxylin and eosin staining based matrigel assay relative to control
|
Homo sapiens
|
55.0
%
|
|
Journal : Eur J Med Chem
Title : Anti-inflammatory hybrids of secondary amines and amide-sulfamide derivatives.
Year : 2018
Volume : 150
First Page : 195
Last Page : 205
Authors : Bai R, Sun J, Liang Z, Yoon Y, Salgado E, Feng A, Oum Y, Xie Y, Shim H.
Abstract : The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells. Additionally, compound 7a blocked mice ear inflammation by 67% and suppressed the accumulation of inflammatory cells in an in vivo mouse ear edema evaluation. Western blot analyses revealed that 7a inhibited the CXCR4/CXCL12-mediated phosphorylation of Akt and p44 in a dose-dependent manner. Moreover, compound 7a had no observable cytotoxicity and displayed a favorable plasma stability in our preliminary pharmacokinetic study. These results confirmed that this is a feasible method to develop CXCR4 modulators for the regulation and reduction of inflammation.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
9.92
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of CXCR4-mediated chemotaxis in human MDA-MB-231 cells assessed as reduction in CXCL12alpha-induced cell invasion after 22 hrs by hematoxylin/eosin dye-based matrigel assay relative to control
|
Homo sapiens
|
53.0
%
|
|
Journal : Eur J Med Chem
Title : Amide-sulfamide modulators as effective anti-tumor metastatic agents targeting CXCR4/CXCL12 axis.
Year : 2020
Volume : 185
First Page : 111823
Last Page : 111823
Authors : Wu R, Yu W, Yao C, Liang Z, Yoon Y, Xie Y, Shim H, Bai R.
Abstract : Breast cancer is the most frequently diagnosed malignancy and the second common cause of death in women worldwide. High mortality in breast cancer is frequently associated with metastatic progression rather than the primary tumor itself. It has been recently identified that the CXCR4/CXCL12 axis plays a pivotal role in breast cancer metastasis, especially in directing metastatic cancer cells to CXCL12-riched organs and tissues. Herein, taking the amide-sulfamide as the lead structure, the second-round structural modifications to the sulfamide structure were performed to obtain more active CXCR4 modulators against tumor metastasis. Both in vivo and in vitro experiments illustrated that compound IIIe possessed potent CXCR4 binding affinity, excellent anti-metastatic and anti-angiogenetic activity against breast cancer. More importantly, in a mouse breast cancer lung metastasis model, compound IIIe exerted a significant inhibitory effect on breast cancer metastasis. Taken together, all these positive results demonstrated that developing of CXCR4 modulators is a promising strategy to mediate breast cancer metastasis.
|
Inhibition of CXCR4-mediated chemotaxis in human MDA-MB-231 cells assessed as reduction in CXCL12alpha-induced cell invasion incubated for 22 hrs by hematoxylin/eosin dye-based matrigel assay relative to control
|
Homo sapiens
|
55.0
%
|
|
Journal : Eur J Med Chem
Title : Development of CXCR4 modulators based on the lead compound RB-108.
Year : 2019
Volume : 173
First Page : 32
Last Page : 43
Authors : Bai R, Jie X, Sun J, Liang Z, Yoon Y, Feng A, Oum Y, Yu W, Wu R, Sun B, Salgado E, Xie Y, Shim H.
Abstract : The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds IIb, IIc, IIIg, IIIj, and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108.
|
Inhibition of CXCR4-mediated chemotaxis in human MDA-MB-231 cells assessed as reduction in CXCL12alpha-induced cell invasion at 100 nM after 22 hrs by hematoxylin/eosin dye-based matrigel assay relative to control
|
Homo sapiens
|
62.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and evaluation of 2,5-diamino and 2,5-dianilinomethyl pyridine analogues as potential CXCR4 antagonists.
Year : 2019
Volume : 29
Issue : 2
First Page : 220
Last Page : 224
Authors : Virani S, Liang Z, Yoon Y, Shim H, Mooring SR.
Abstract : CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.
|
Displacement of [125I]-CXCL12 from human CXCR4 receptor expressed in HEK293T cell membranes after 2 hrs by scintillation counting analysis
|
Homo sapiens
|
199.53
nM
|
|
Journal : Eur J Med Chem
Title : Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists.
Year : 2019
Volume : 162
First Page : 631
Last Page : 649
Authors : Adlere I, Sun S, Zarca A, Roumen L, Gozelle M, Viciano CP, Caspar B, Arimont M, Bebelman JP, Briddon SJ, Hoffmann C, Hill SJ, Smit MJ, Vischer HF, Wijtmans M, de Graaf C, de Esch IJP, Leurs R.
Abstract : Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.
|
Displacement of [125I]-CXCL12 from human CXCR4 receptor expressed in HEK293T cell membranes at 63 uM after 2 hrs by scintillation counting analysis relative to IT1t
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur J Med Chem
Title : Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists.
Year : 2019
Volume : 162
First Page : 631
Last Page : 649
Authors : Adlere I, Sun S, Zarca A, Roumen L, Gozelle M, Viciano CP, Caspar B, Arimont M, Bebelman JP, Briddon SJ, Hoffmann C, Hill SJ, Smit MJ, Vischer HF, Wijtmans M, de Graaf C, de Esch IJP, Leurs R.
Abstract : Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.
|
Competitive binding affinity to CXCR4 in human SupT1 cells incubated for 40 mins by 12G5 antibody based fluorescence analysis
|
Homo sapiens
|
44.0
nM
|
|
Journal : Eur J Med Chem
Title : High affinity CXCR4 inhibitors generated by linking low affinity peptides.
Year : 2019
Volume : 172
First Page : 174
Last Page : 185
Authors : Zhang C, Huang LS, Zhu R, Meng Q, Zhu S, Xu Y, Zhang H, Fang X, Zhang X, Zhou J, Schooley RT, Yang X, Huang Z, An J.
Abstract : G-protein coupled receptors (GPCRs) are implicated in many diseases and attractive targets for drug discovery. Peptide fragments derived from protein ligands of GPCRs are commonly used as probes of GPCR function and as leads for drug development. However, these peptide fragments lack the structural integrity of their parent full-length protein ligands and often show low receptor affinity, which limits their research and therapeutic values. It remains a challenge to efficiently generate high affinity peptide inhibitors of GPCRs. We have investigated a combinational approach involving the synthetic covalent linkage of two low affinity peptide fragments to determine if the strategy can yield high affinity GPCR inhibitors. We examined this design approach using the chemokine receptor CXCR4 as a model of GPCR system. Here, we provide a proof of concept demonstration by designing and synthesizing two peptides, AR5 and AR6, that combine a peptide fragment derived from two viral ligands of CXCR4, vMIP-II and HIV-1 envelope glycoprotein gp120. AR5 and AR6 display nanomolar binding affinity, in contrast to the weak micromolar CXCR4 binding of each peptide fragment alone, and inhibit HIV-1 entry via CXCR4. Further studies were carried out for the representative peptide AR6 using western blotting and site-directed mutagenesis in conjunction with molecular dynamic simulation and binding free energy calculation to determine how the peptide interacts with CXCR4 and inhibits its downstream signaling. These results demonstrate that this combinational approach is effective for generating nanomolar active inhibitors of CXCR4 and may be applicable to other GPCRs.
|
Competitive binding affinity to CXCR4 receptor (unknown origin) expressed in CHO cells incubated for 40 mins by 12G5 antibody based fluorescence analysis
|
Homo sapiens
|
51.0
nM
|
|
Journal : Eur J Med Chem
Title : High affinity CXCR4 inhibitors generated by linking low affinity peptides.
Year : 2019
Volume : 172
First Page : 174
Last Page : 185
Authors : Zhang C, Huang LS, Zhu R, Meng Q, Zhu S, Xu Y, Zhang H, Fang X, Zhang X, Zhou J, Schooley RT, Yang X, Huang Z, An J.
Abstract : G-protein coupled receptors (GPCRs) are implicated in many diseases and attractive targets for drug discovery. Peptide fragments derived from protein ligands of GPCRs are commonly used as probes of GPCR function and as leads for drug development. However, these peptide fragments lack the structural integrity of their parent full-length protein ligands and often show low receptor affinity, which limits their research and therapeutic values. It remains a challenge to efficiently generate high affinity peptide inhibitors of GPCRs. We have investigated a combinational approach involving the synthetic covalent linkage of two low affinity peptide fragments to determine if the strategy can yield high affinity GPCR inhibitors. We examined this design approach using the chemokine receptor CXCR4 as a model of GPCR system. Here, we provide a proof of concept demonstration by designing and synthesizing two peptides, AR5 and AR6, that combine a peptide fragment derived from two viral ligands of CXCR4, vMIP-II and HIV-1 envelope glycoprotein gp120. AR5 and AR6 display nanomolar binding affinity, in contrast to the weak micromolar CXCR4 binding of each peptide fragment alone, and inhibit HIV-1 entry via CXCR4. Further studies were carried out for the representative peptide AR6 using western blotting and site-directed mutagenesis in conjunction with molecular dynamic simulation and binding free energy calculation to determine how the peptide interacts with CXCR4 and inhibits its downstream signaling. These results demonstrate that this combinational approach is effective for generating nanomolar active inhibitors of CXCR4 and may be applicable to other GPCRs.
|
Binding affinity to CXCR4 (unknown origin) expressed in CHO cells measured after 40 mins by 12G5 antibody competition assay
|
Homo sapiens
|
65.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and biological characterization of novel PEG-linked dimeric modulators for CXCR4.
Year : 2016
Volume : 24
Issue : 21
First Page : 5393
Last Page : 5399
Authors : Yang Y, Gao M, Zhang Q, Zhang C, Yang X, Huang Z, An J.
Abstract : CXCR4 dimerization has been widely demonstrated both biologically and structurally. This paper mainly focused on the development of structure-based dimeric ligands that target CXCL12-CXCR4 interaction and signaling. This study presents the design and synthesis of a series of [PEG]<sub>n</sub> linked dimeric ligands of CXCR4 based on the knowledge of the homodimeric crystal structure of CXCR4 and our well established platform of chemistry and bioassays for CXCR4. These new ligands include [PEG]<sub>n</sub> linked homodimeric or heterodimeric peptides consisting of either two DV3-derived moieties (where DV3 is an all-d-amino acid analog of N-terminal modules of 1-10 (V3) residues of vMIP-II) or hybrids of DV3 moieties and CXCL12<sub>1</sub><sub>-</sub><sub>8</sub>. Among a total of 24 peptide ligands, four antagonists and three agonists showed good CXCR4 binding affinity, with IC<sub>50</sub> values of <50nM and <800nM, respectively. Chemotaxis and calcium mobilization assays with SUP-T1 cells further identified two promising lead modulators of CXCR4: ligand 4, a [PEG<sub>3</sub>]<sub>2</sub> linked homodimeric DV3, was an effective CXCR4 antagonist (IC<sub>50</sub>=22nM); and ligand 21, a [PEG<sub>3</sub>]<sub>2</sub> linked heterodimeric DV3-CXCL12<sub>1</sub><sub>-</sub><sub>8</sub>, was an effective CXCR4 agonist (IC<sub>50</sub>=407nM). These dimeric CXCR4 modulators represent new molecular probes and therapeutics that effectively modulate CXCL12-CXCR4 interaction and function.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.88
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.24
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antiviral activity against HIV-1 NL4-3 in human MT-4 cells assessed as virus induced cytopathic effect incubated for 5 days by MTT assay
|
Human immunodeficiency virus 1
|
49.0
nM
|
|
Journal : Bioorg Med Chem
Title : Potent leads based on CA-19L, an anti-HIV active HIV-1 capsid fragment.
Year : 2021
Volume : 30
First Page : 115923
Last Page : 115923
Authors : Tsuji K,Wang R,Kobayakawa T,Owusu KB,Fujino M,Kaneko M,Yamamoto N,Murakami T,Tamamura H
Abstract : Several anti-HIV-1 peptides have previously been found among overlapping fragment peptide libraries that contain an octa-arginyl moiety and cover the whole sequence of an HIV-1 capsid (CA) protein. Several derivatives based on a potent CA fragment peptide CA-19L have been synthesized. CA-19L overlaps with the Helix 9 region of the CA protein, which could be important for oligomerization of the CA proteins. Derivatives of CA-19L in which several amino acid residues were added to the N- and C-termini according to the natural CA sequence, were synthesized and their anti-HIV activity was evaluated. Some potent compounds were found, and these potential new anti-HIV agents are expected to be useful as new tools for elucidation of CA functions.
|
Antagonist activity at CXCR4 in human CD4-positive T cells assessed as inhibition of CXCL12-induced calcium signal incubated for 20 mins by FLIPR assay
|
Homo sapiens
|
6.134
nM
|
|
Journal : Eur J Med Chem
Title : Structural optimization of aminopyrimidine-based CXCR4 antagonists.
Year : 2020
Volume : 187
First Page : 111914
Last Page : 111914
Authors : Zhu,F.; Wang,Y.; Du,Q.; Ge,W.; Li,Z.; Wang,X.; Fu,C.; Luo,L.; Tian,S.; Ma,H.; Zheng,J.; Zhang,Y.; Sun,X.; He,S.; Zhang,X.
Abstract : Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.
|
Antagonist activity at CXCR4 in human HPBALL cells assessed as inhibition of APC-conjugate clone 12G5 antibody signal incubated for 3 hrs by flow cytometric analysis
|
Homo sapiens
|
303.0
nM
|
|
Journal : Eur J Med Chem
Title : Structural optimization of aminopyrimidine-based CXCR4 antagonists.
Year : 2020
Volume : 187
First Page : 111914
Last Page : 111914
Authors : Zhu,F.; Wang,Y.; Du,Q.; Ge,W.; Li,Z.; Wang,X.; Fu,C.; Luo,L.; Tian,S.; Ma,H.; Zheng,J.; Zhang,Y.; Sun,X.; He,S.; Zhang,X.
Abstract : Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.
|
Antiviral activity against Human immunodeficiency virus 1 NL4-3 infected in human MT4 cells assessed as reduction in virus-induced cytopathogenicity measured after 5 days by MTT assay
|
Human immunodeficiency virus 1
|
35.0
nM
|
|
Journal : Bioorg Med Chem
Title : Exploratory studies on CA-15L, an anti-HIV active HIV-1 capsid fragment.
Year : 2020
Volume : 28
Issue : 11
First Page : 115488
Last Page : 115488
Authors : Tsuji K,Owusu KB,Kobayakawa T,Wang R,Fujino M,Kaneko M,Yamamoto N,Murakami T,Tamamura H
Abstract : Utilizing overlapping fragment peptide libraries covering the whole sequence of an HIV-1 capsid (CA) protein with the addition of an octa-arginyl moiety, we had previously found several peptides with anti-HIV-1 activity. Herein, among these potent CA fragment peptides, CA-15L was examined because this peptide sequence overlaps with Helix 7, a helix region of the CA protein, which may be important for oligomerization of the CA proteins. A CA-15L surrogate with hydrophilic residues, and its derivatives, in which amino acid sequences are shifted toward the C-terminus by one or more residues, were synthesized and their anti-HIV activity was evaluated. In addition, its derivatives with substitution for the Ser149 residue were synthesized and their anti-HIV activity was evaluated because Ser149 might be phosphorylated in the step of degradation of CA protein oligomers. Several active compounds were found and might become new anti-HIV agents and new tools for elucidation of CA functions.
|
Inhibition of APC-conjugated anti-human CXCR4 clone 12G5 binding to CXCR4 in human HPBALL cells measured after 3 hrs by FACS analysis
|
Homo sapiens
|
561.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity.
Year : 2020
Volume : 205
First Page : 112537
Last Page : 112537
Authors : Li Z,Wang X,Lin Y,Wang Y,Wu S,Xia K,Xu C,Ma H,Zheng J,Luo L,Zhu F,He S,Zhang X
Abstract : The chemokine receptor CXCR4 has been proposed as a drug target based on its important functions in HIV infection, inflammation/autoimmune diseases and cancer metastasis. Herein we report the design, synthesis and evaluation of novel CXCR4 antagonists based on a pyrrolidine scaffold. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by compound 46, which displayed potent binding affinity to CXCR4 receptor (IC = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC = 0.25 nM). Moreover, in a transwell invasion assay, compound 46 significantly mitigated CXCL12/CXCR4 mediated cell migration. Compound 46 exhibited good physicochemical properties (MW 367, logD 1.12, pKa 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC > 30 μM and minimal CYP isozyme inhibition). Importantly, 46 displayed much improved metabolic stability in human and rat liver microsomes. Lastly, 46 demonstrated marked efficacy in a cancer metastasis model in mice. These results strongly support 46 as a prototypical lead for the development of promising CXCR4 antagonists as clinical candidates.
|
Antagonist activity at CXCR4 in human CD4-positive T cells assessed as inhibition of CXCL12-induced cytosolic calcium flux preincubated for 20 mins followed by CXCL12 addition by calcium 4 dye based FLIPR TETRA analysis
|
Homo sapiens
|
6.134
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity.
Year : 2020
Volume : 205
First Page : 112537
Last Page : 112537
Authors : Li Z,Wang X,Lin Y,Wang Y,Wu S,Xia K,Xu C,Ma H,Zheng J,Luo L,Zhu F,He S,Zhang X
Abstract : The chemokine receptor CXCR4 has been proposed as a drug target based on its important functions in HIV infection, inflammation/autoimmune diseases and cancer metastasis. Herein we report the design, synthesis and evaluation of novel CXCR4 antagonists based on a pyrrolidine scaffold. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by compound 46, which displayed potent binding affinity to CXCR4 receptor (IC = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC = 0.25 nM). Moreover, in a transwell invasion assay, compound 46 significantly mitigated CXCL12/CXCR4 mediated cell migration. Compound 46 exhibited good physicochemical properties (MW 367, logD 1.12, pKa 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC > 30 μM and minimal CYP isozyme inhibition). Importantly, 46 displayed much improved metabolic stability in human and rat liver microsomes. Lastly, 46 demonstrated marked efficacy in a cancer metastasis model in mice. These results strongly support 46 as a prototypical lead for the development of promising CXCR4 antagonists as clinical candidates.
|
Anti-HIV activity against HIV-1 NL4.3 infected in PHA-stimulated human PBMC expressing CXCR-4 assessed as inhibition of virus-indued cytopathogenic effect measured after 10 days by ELISA
|
Human immunodeficiency virus 1
|
0.00357
ug.mL-1
|
|
|
Anti-HIV activity against HIV-1 Ba-L infected in PHA-stimulated PBMC expressing CCR5 assessed as inhibition of virus-indued cytopathogenic effect measured after 10 days by ELISA
|
Human immunodeficiency virus 1
|
1.0
ug.mL-1
|
|
