|
Tested for the effective concentration required to inhibit HBV in HepG2.2.15 human liver cells
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : BMS-200475, a novel carbocyclic 2-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro
Year : 1997
Volume : 7
Issue : 2
First Page : 127
Last Page : 132
Authors : Bisacchi G, Chao S, Bachard C, Daris J, Innaimo S, Jacobs G, Kocy O, Lapointe P, Martel A, Merchant Z, Slusarchyk W, Sundeen J, Young M, Colonno R, Zahler R
|
Inhibition of HBV replication with RT A200V substitution from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
7.6
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT A200V substitution and M204I background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
33.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT A200V substitution and L180M, M204I background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT L80V substitution and L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
11.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT V27A substitution and L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT I53F substitution and V173F, L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
22.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT S78T substitution from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
2.4
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT L80I substitution and L180M, M204I background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
45.3
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT K168E substitution and M204I background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT A181T substitution and V173L, L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
14.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT C188S substitution and L80I, L180T, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
31.2
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT V224A substitution and V173L, L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT L228P substitution and M204I background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT L229W substitution and L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
32.9
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT D263G substitution from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
5.8
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT Q267Stop substitution and L180M, M204V background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT G295S substitution and L80I, M204I background from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of HBV replication with RT M309L substitution from Lamivudine refractory patient transfected into HepG2 cells
|
Hepatitis B virus
|
4.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Two-year assessment of entecavir resistance in Lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present.
Year : 2007
Volume : 51
Issue : 3
First Page : 902
Last Page : 911
Authors : Tenney DJ, Rose RE, Baldick CJ, Levine SM, Pokornowski KA, Walsh AW, Fang J, Yu CF, Zhang S, Mazzucco CE, Eggers B, Hsu M, Plym MJ, Poundstone P, Yang J, Colonno RJ.
Abstract : Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV). In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.
|
Inhibition of wild type HBV replication in Huh7 cells
|
Hepatitis B virus
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants.
Year : 2007
Volume : 51
Issue : 6
First Page : 2240
Last Page : 2243
Authors : Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, Zoulim F.
Abstract : The susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
|
Antiviral activity against wild type HBV assessed as inhibition of replication
|
Hepatitis B virus
|
800.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants.
Year : 2007
Volume : 51
Issue : 6
First Page : 2240
Last Page : 2243
Authors : Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, Zoulim F.
Abstract : The susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
|
Antiviral activity against adenofir-resistant HBV with reverse transcriptase N236T mutant assessed as inhibition of replication
|
Hepatitis B virus
|
700.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants.
Year : 2007
Volume : 51
Issue : 6
First Page : 2240
Last Page : 2243
Authors : Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, Zoulim F.
Abstract : The susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
|
Antiviral activity against wild type HBV genotype H assessed as inhibition of replication
|
Hepatitis B virus
|
90.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants.
Year : 2007
Volume : 51
Issue : 6
First Page : 2240
Last Page : 2243
Authors : Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, Zoulim F.
Abstract : The susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
|
Antiviral activity against wild type HBV genotype E assessed as inhibition of replication
|
Hepatitis B virus
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants.
Year : 2007
Volume : 51
Issue : 6
First Page : 2240
Last Page : 2243
Authors : Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, Zoulim F.
Abstract : The susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
|
Antiviral activity against lamivudine-adenofir-resistant HBV with reverse transcriptase V173L/L180M/A181V/N236T mutant
|
Hepatitis B virus
|
500.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants.
Year : 2007
Volume : 51
Issue : 6
First Page : 2240
Last Page : 2243
Authors : Brunelle MN, Lucifora J, Neyts J, Villet S, Holy A, Trepo C, Zoulim F.
Abstract : The susceptibilities of drug-resistant hepatitis B virus (HBV) mutants to lamivudine, adefovir, tenofovir, entecavir, and 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine (PMEO-DAPym), a novel acyclic pyrimidine analogue, were assessed in vitro. Most drug-resistant mutants, including multidrug-resistant strains, remained sensitive to tenofovir and PMEO-DAPym. Therefore, the latter molecule deserves further evaluation for the treatment of HBV infection.
|
Antiviral activity against Hepatitis B virus
|
Hepatitis B virus
|
4.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-RF infected in 1 hr-pretreated human MT2 cells assessed as inhibition of multicycle replication measured on day 5 postinfection by RT SPA
|
Human immunodeficiency virus 1
|
839.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-SF-2 infected in 1 hr-pretreated human MT2 cells assessed as inhibition of multicycle replication measured on day 5 postinfection by RT SPA
|
Human immunodeficiency virus 1
|
526.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-3B infected in 1 hr-pretreated human MT2 cells assessed as inhibition of multicycle replication measured on day 5 postinfection by RT SPA
|
Human immunodeficiency virus 1
|
81.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-LAI infected in 1 hr-pretreated human MT2 cells assessed as inhibition of multicycle replication measured on day 5 postinfection by RT SPA
|
Human immunodeficiency virus 1
|
71.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-NL4-3 infected in 1 hr-pretreated human MT2 cells assessed as inhibition of multicycle replication measured on day 5 postinfection by RT SPA
|
Human immunodeficiency virus 1
|
85.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-ASM 034 infected in 1 hr-pretreated PBMC cells assessed as inhibition of p24 antigen production measured on day 5 postinfection by ELISA
|
Human immunodeficiency virus 1
|
109.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-92US076 infected in 1 hr-pretreated PBMC cells assessed as inhibition of p24 antigen production measured on day 5 postinfection by ELISA
|
Human immunodeficiency virus 1
|
62.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV1 subtype B-ASM 044 infected in 1 hr-pretreated PBMC cells assessed as inhibition of p24 antigen production measured on day 5 postinfection by ELISA
|
Human immunodeficiency virus 1
|
26.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against 0.005 MOI wild type HIV1 NL4-3 infected in human MT2 cells measured after 5 days by RT SPA
|
Human immunodeficiency virus 1
|
56.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against 0.01 MOI wild type HIV1 NL4-3 infected in human MT2 cells measured after 5 days by RT SPA
|
Human immunodeficiency virus 1
|
95.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against 0.02 MOI wild type HIV1 NL4-3 infected in human MT2 cells measured after 5 days by RT SPA
|
Human immunodeficiency virus 1
|
449.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against 0.006 MOI HIV1 NL4-3 infected in human MT2 cells measured after 5 days by RT SPA
|
Human immunodeficiency virus 1
|
151.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against 0.006 MOI HIV1 NL4-3 infected in 1 hr-pretreated human MT2 cells measured after 5 days by RT SPA
|
Human immunodeficiency virus 1
|
287.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against 0.005 MOI HIV1 NL4-3 harboring wild type RT infected in human MT2 cells
|
Human immunodeficiency virus 1
|
56.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against HIV infected in CD4+ lymphocyte by fluorescence-activated cell sorter assay
|
Human immunodeficiency virus
|
0.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Entecavir exhibits inhibitory activity against human immunodeficiency virus under conditions of reduced viral challenge.
Year : 2008
Volume : 52
Issue : 5
First Page : 1759
Last Page : 1767
Authors : Lin PF, Nowicka-Sans B, Terry B, Zhang S, Wang C, Fan L, Dicker I, Gali V, Higley H, Parkin N, Tenney D, Krystal M, Colonno R.
Abstract : Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
|
Antiviral activity against wild type Hepatitis B virus infected in human HepG2(2.2.15) cells assessed as inhibition of virus replication treated daily for 9 days by quantitative blot hybridization method
|
Hepatitis B virus
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiviral activity of novel 2'-fluoro-6'-methylene-carbocyclic adenosine against wild-type and drug-resistant hepatitis B virus mutants.
Year : 2011
Volume : 21
Issue : 21
First Page : 6328
Last Page : 6331
Authors : Wang J, Singh US, Rawal RK, Sugiyama M, Yoo J, Jha AK, Scroggin M, Huang Z, Murray MG, Govindarajan R, Tanaka Y, Korba B, Chu CK.
Abstract : Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (9) was synthesized and evaluated its anti-HBV activity. The titled compound demonstrated significant antiviral activity against wild-type as well as lamivudine, adefovir and double lamivudine/entecavir resistant mutants. Molecular modeling study indicate that the 2'-fluoro moiety by a hydrogen bond, as well as the van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug resistant mutants.
|
Antiviral activity against wild type Hepatitis B virus infected in human HuH7 cells
|
Hepatitis B virus
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: in vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action.
Year : 2013
Volume : 23
Issue : 2
First Page : 503
Last Page : 506
Authors : Rawal RK, Singh US, Chavre SN, Wang J, Sugiyama M, Hung W, Govindarajan R, Korba B, Tanaka Y, Chu CK.
Abstract : Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (FMCA) monophosphate prodrug (FMCAP) was synthesized and evaluated for its in vitro anti-HBV potency against a lamivudine-entecavir resistant clone (L180M+M204V+S202G). FMCA demonstrated significant antiviral activity against wild-type as well as lamivudine-entecavir resistant triple mutant (L180M+M204V+S202G). The monophosphate prodrug (FMCAP) demonstrated greater than 12-fold (12×) increase in anti-HBV activity without increased cellular toxicity. Mitochondrial and cellular toxicity studies of FMCA indicated that there is no significant toxicity up to 100 μM. Mode of action studies by molecular modeling indicate that the 2'-fluoro moiety by hydrogen bond as well as the Van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug-resistant mutants.
|
Antiviral activity against Hepatitis B virus in HepG2.CW cells assessed as inhibition of viral DNA replication at 1 uM after 9 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
95.7
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against Hepatitis B virus in HepG2.2.15 cells assessed as inhibition of intracellular viral DNA replication at 0.1 uM after 3 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
37.8
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against Hepatitis B virus in HepG2.2.15 cells assessed as inhibition of intracellular viral DNA replication at 0.1 uM after 6 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
40.6
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against Hepatitis B virus in HepG2.2.15 cells assessed as inhibition of intracellular viral DNA replication at 0.1 uM after 9 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
57.6
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against Hepatitis B virus in HepG2.2.15 cells assessed as inhibition of extracellular viral DNA replication at 0.1 uM after 3 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
38.2
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against Hepatitis B virus in HepG2.2.15 cells assessed as inhibition of extracellular viral DNA replication at 0.1 uM after 6 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
47.8
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against Hepatitis B virus in HepG2.2.15 cells assessed as inhibition of extracellular viral DNA replication at 0.1 uM after 9 days by real-time FQ-PCR analysis
|
Hepatitis B virus
|
78.6
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and biological evaluation of 4-substituted fluoronucleoside analogs for the treatment of hepatitis B virus infection.
Year : 2015
Volume : 58
Issue : 9
First Page : 3693
Last Page : 3703
Authors : Yang Q, Kang J, Zheng L, Wang XJ, Wan N, Wu J, Qiao Y, Niu P, Wang SQ, Peng Y, Wang Q, Yu W, Chang J.
Abstract : A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.
|
Antiviral activity against HBV ayw1 infected in human HepG2(2.2.15) cells assessed as reduction in viral replication by measuring extracellular viral DNA copy number after 6 days by real-time qPCR method
|
Hepatitis B virus
|
10.0
nM
|
|
Journal : J Med Chem
Title : Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.
Year : 2017
Volume : 60
Issue : 14
First Page : 6220
Last Page : 6238
Authors : Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P.
Abstract : Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
|
Antiviral activity against HBV ayw1 infected in human HepG2(2.2.15) cells assessed as reduction in viral replication by measuring intracellular viral DNA copy number after 6 days byr by real-time qPCR assay
|
Hepatitis B virus
|
0.35
nM
|
|
Journal : J Med Chem
Title : Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.
Year : 2017
Volume : 60
Issue : 14
First Page : 6220
Last Page : 6238
Authors : Luo M, Groaz E, Andrei G, Snoeck R, Kalkeri R, Ptak RG, Hartman T, Buckheit RW, Schols D, De Jonghe S, Herdewijn P.
Abstract : Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.
|
Antiviral activity against HBV infected in human HepG2(2.2.15) cells assessed as inhibition of viral DNA replication at 10 uM after 72 hrs by RT-PCR method relative to control
|
Hepatitis B virus
|
95.67
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of novel phenyl propionamide derivatives as non-nucleoside hepatitis B virus inhibitors.
Year : 2018
Volume : 144
First Page : 424
Last Page : 434
Authors : Qiu J, Gong Q, Gao J, Chen W, Zhang Y, Gu X, Tang D.
Abstract : As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 μM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 μM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.
|
Antiviral activity against lamivudine/entecavir resistant HBV harboring reverse transcriptase L180M/M204V/T184L mutant infected in human HepG2(2.2.15) cells assessed as inhibition of viral DNA replication at 10 uM after 72 hrs by RT-PCR method relative to control
|
Hepatitis B virus
|
17.9
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of novel phenyl propionamide derivatives as non-nucleoside hepatitis B virus inhibitors.
Year : 2018
Volume : 144
First Page : 424
Last Page : 434
Authors : Qiu J, Gong Q, Gao J, Chen W, Zhang Y, Gu X, Tang D.
Abstract : As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 μM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153.14, suggesting that 8d and 9b exhibited favorable safety profiles. Interestingly, 8d and 9b possessed significantly antiviral activities against lamivudine and entecavir resistant HBV mutants with IC50 values of 0.77 and 0.32 μM. Notably, preliminary anti-HBV action mechanism studies showed that 8d could inhibit intracellular HBV pgRNA and RT activity of the HBV polymerase. Molecular docking studies suggested that compound 8d could fit into the dimer-dimer interface of HBV core protein by hydrophobic interaction. In addition, in silico prediction of physicochemical properties showed that 8d conformed well to the Lipinski's rule of five, suggesting its potential for use as a drug like molecule. Taken together, 8d possessed significantly anti-HBV activity, low toxicity, diverse anti-HBV mechanism and favorable physicochemical properties, and warranted further investigation as a promising non-nucleoside anti-HBV candidate.
|
Inhibition of hepatitis B virus capsid assembly infected in human HepG2.215 cells assessed as reduction in viral DNA replication measured on day 7 by real time PCR analysis
|
Hepatitis B virus
|
0.24
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4).
Year : 2017
Volume : 25
Issue : 3
First Page : 1042
Last Page : 1056
Authors : Ren Q, Liu X, Luo Z, Li J, Wang C, Goldmann S, Zhang J, Zhang Y.
Abstract : Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4-[2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro-pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC50 value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 values in the range of 10-20nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human.
|
Antiviral activity against entecavir-resistant wild type hepatitis B virus infected in human Huh7 cells assessed as reduction in intracellular DNA levels measured on day 7 by real-time PCR analysis
|
Hepatitis B virus
|
13.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4).
Year : 2017
Volume : 25
Issue : 3
First Page : 1042
Last Page : 1056
Authors : Ren Q, Liu X, Luo Z, Li J, Wang C, Goldmann S, Zhang J, Zhang Y.
Abstract : Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4-[2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro-pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC50 value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 values in the range of 10-20nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human.
|
Antiviral activity against entecavir-resistant wild type hepatitis B virus infected in human Huh7 cells assessed as reduction in secreted DNA levels measured on day 7 by real-time PCR analysis
|
Hepatitis B virus
|
14.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4).
Year : 2017
Volume : 25
Issue : 3
First Page : 1042
Last Page : 1056
Authors : Ren Q, Liu X, Luo Z, Li J, Wang C, Goldmann S, Zhang J, Zhang Y.
Abstract : Inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. Herein we described our lead optimization studies including the synthesis, molecular docking studies and structure-activity relationship (SAR) studies of a series of novel heteroaryldihydropyrimidine (HAP) inhibitors of HBV capsid assembly inhibitors, and the discovery of a potent inhibitor of HBV capsid assembly of GLS4 (ethyl 4-[2-bromo-4-fluorophenyl]-6-[morpholino-methyl]-2-[2-thiazolyl]-1,4-dihydro-pyrimidine-5-carboxylate) which is now in clinical phase 2. GLS4 demonstrated potent inhibitory activities in HBV HepG2.2.15 cell assay with an EC50 value of 1nM, and it also exhibited high potency against various drug-resistant HBV viral strains with EC50 values in the range of 10-20nM, more potent than the typical HBV polymerase inhibitors such as lamivudine, telbivudine, and entecavir. Pharmacokinetic profiles of GLS4 were favorable and safety evaluation including acute toxicity and repeated toxicity study indicated that GLS4 was safe enough to support clinical experiments in human.
|
Inhibition of capsid in HBV infected in human HepAD38 cells assessed as reduction in cccDNA formation by measuring reduction in HBe antigen secretion at 10 uM after 14 days by ELISA relative to control
|
Hepatitis B virus
|
1.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis of sulfamoylbenzamide derivatives as HBV capsid assembly effector.
Year : 2017
Volume : 138
First Page : 407
Last Page : 421
Authors : Sari O, Boucle S, Cox BD, Ozturk T, Russell OO, Bassit L, Amblard F, Schinazi RF.
Abstract : The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion. Selected compounds were studied under negative-stain electron microscopy for their ability to disrupt the HBV capsid formation. Structures were modeled into a binding site recently identified in the HBV capsid protein for similar molecules to rationalize the structure-activity relationships for this family of compounds.
|
Antiviral activity against HBV infected in human HepAD38 cells assessed as reduction in extracellular viral DNA level by RT-PCR method
|
Hepatitis B virus
|
0.7
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of sulfamoylbenzamide derivatives as HBV capsid assembly effector.
Year : 2017
Volume : 138
First Page : 407
Last Page : 421
Authors : Sari O, Boucle S, Cox BD, Ozturk T, Russell OO, Bassit L, Amblard F, Schinazi RF.
Abstract : The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion. Selected compounds were studied under negative-stain electron microscopy for their ability to disrupt the HBV capsid formation. Structures were modeled into a binding site recently identified in the HBV capsid protein for similar molecules to rationalize the structure-activity relationships for this family of compounds.
|
Antiviral activity against HBV infected in human HepAD38 cells assessed as reduction in intracellular viral DNA level by RT-PCR method
|
Hepatitis B virus
|
0.1
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis of sulfamoylbenzamide derivatives as HBV capsid assembly effector.
Year : 2017
Volume : 138
First Page : 407
Last Page : 421
Authors : Sari O, Boucle S, Cox BD, Ozturk T, Russell OO, Bassit L, Amblard F, Schinazi RF.
Abstract : The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion. Selected compounds were studied under negative-stain electron microscopy for their ability to disrupt the HBV capsid formation. Structures were modeled into a binding site recently identified in the HBV capsid protein for similar molecules to rationalize the structure-activity relationships for this family of compounds.
|
Antiviral activity against Hepatitis B virus infected in human dHepaRG cells assessed as reduction in HBsAg secretion after 10 mins by chemiluminescence immunoassay
|
Hepatitis B virus
|
1.0
nM
|
|
Journal : J Med Chem
Title : Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action.
Year : 2018
Volume : 61
Issue : 23
First Page : 10619
Last Page : 10634
Authors : Han X, Zhou C, Jiang M, Wang Y, Wang J, Cheng Z, Wang M, Liu Y, Liang C, Wang J, Wang Z, Weikert R, Lv W, Xie J, Yu X, Zhou X, Luangsay S, Shen HC, Mayweg AV, Javanbakht H, Yang S.
Abstract : Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.
|
Antiviral activity against Hepatitis B virus infected in human dHepaRG cells assessed as reduction in HBeAg secretion after 10 mins by chemiluminescence immunoassay
|
Hepatitis B virus
|
1.0
nM
|
|
Journal : J Med Chem
Title : Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action.
Year : 2018
Volume : 61
Issue : 23
First Page : 10619
Last Page : 10634
Authors : Han X, Zhou C, Jiang M, Wang Y, Wang J, Cheng Z, Wang M, Liu Y, Liang C, Wang J, Wang Z, Weikert R, Lv W, Xie J, Yu X, Zhou X, Luangsay S, Shen HC, Mayweg AV, Javanbakht H, Yang S.
Abstract : Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.
|
Antiviral activity against Hepatitis B virus infected in human dHepaRG cells assessed as reduction in extracellular viral DNA levels after 6 days by qPCR/TaqMan assay
|
Hepatitis B virus
|
0.06
nM
|
|
Journal : J Med Chem
Title : Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action.
Year : 2018
Volume : 61
Issue : 23
First Page : 10619
Last Page : 10634
Authors : Han X, Zhou C, Jiang M, Wang Y, Wang J, Cheng Z, Wang M, Liu Y, Liang C, Wang J, Wang Z, Weikert R, Lv W, Xie J, Yu X, Zhou X, Luangsay S, Shen HC, Mayweg AV, Javanbakht H, Yang S.
Abstract : Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure-activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.
|
Antiviral activity against HBV genotype D infected in human HepG2.2.15 cells assessed as reduction in viral DNA level after 7 days by RT-PCR assay
|
HBV genotype D
|
3.8
nM
|
|
Journal : ACS Med Chem Lett
Title : Synthesis, Anti-HBV, and Anti-HIV Activities of 3'-Halogenated Bis(hydroxymethyl)-cyclopentenyladenines.
Year : 2018
Volume : 9
Issue : 12
First Page : 1211
Last Page : 1216
Authors : Kumamoto H, Imoto S, Amano M, Kuwata-Higashi N, Baba M, Mitsuya H, Odanaka Y, Shimbara Matsubayashi S, Tanaka H, Haraguchi K.
Abstract : Synthesis of 3'-halogeno analogues (<b>5a</b>-<b>d</b>) of 9-[<i>c</i>-4,<i>t</i>-5-bis(hydroxymethyl)-cyclopent-2-en-<i>r</i>-1-yl]-9<i>H</i>-adenine (BCA, <b>3</b>) was accomplished by means of dual utilization of the vinyl sulfone functional moieties in both <b>10</b> and <b>16</b> utilizing a S<sub>N</sub>2' conjugate-addition reaction and a sulfur-extrusive stannylation, respectively. Evaluation of the antiviral activities of <b>5a</b>-<b>d</b> revealed that introduction of a halogeno-substituent into the 3'-position of (-)-BCA diminished its anti-HIV-1 activity but increased the inhibitory activity for the reverse transcriptase of HBV in that the 3'-fluorinated BCA <b>5d</b> exhibited the highest activity without significant cytotoxicity.
|
Inhibition of capsid protein in lamivudine/entecavir-resistant Hepatitis B virus harboring rtL180M/rtM204V/rt184L mutant infected in human HepG2.2.15 cells assessed as reduction in viral DNA level at 10 uM measured after 72 hrs by PCR analysis relative to control
|
Hepatitis B virus
|
22.58
%
|
|
Journal : Eur J Med Chem
Title : Assessment of quinazolinone derivatives as novel non-nucleoside hepatitis B virus inhibitors.
Year : 2019
Volume : 176
First Page : 41
Last Page : 49
Authors : Qiu J, Chen W, Zhang Y, Zhou Q, Chen J, Yang L, Gao J, Gu X, Tang D.
Abstract : Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC<sub>50</sub> values of 1.54 μM and 0.71 μM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC<sub>50</sub> values of 1.90 and 0.84 μM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.
|
Inhibition of capsid protein in wild type Hepatitis B virus infected in human HepG2.2.15 cells assessed as reduction of viral DNA level at 10 uM measured after 72 hrs by PCR analysis relative to control
|
Hepatitis B virus
|
98.07
%
|
|
Journal : Eur J Med Chem
Title : Assessment of quinazolinone derivatives as novel non-nucleoside hepatitis B virus inhibitors.
Year : 2019
Volume : 176
First Page : 41
Last Page : 49
Authors : Qiu J, Chen W, Zhang Y, Zhou Q, Chen J, Yang L, Gao J, Gu X, Tang D.
Abstract : Hepatitis B virus (HBV) infection is a worldwide public health issue. Search for novel non-nucleoside anti-HBV agents is of great importance. In the present study, a series of quinazolinones derivatives (4a-t and 5a-f) were synthesized and evaluated as novel anti-HBV agents. Among them, compounds 5e and 5f could significantly inhibit HBV DNA replication with IC<sub>50</sub> values of 1.54 μM and 0.71 μM, respectively. Interestingly, the selective index values of 5f was higher than that of lead compound K284-1405, suggesting 5f possessed relatively safety profile than K284-1405. Notably, 5e and 5f exhibited remarkably anti-HBV activities against lamivudine and entecavir resistant HBV strain with IC<sub>50</sub> values of 1.90 and 0.84 μM, confirming their effectiveness against resistant HBV strain. In addition, molecular docking studies indicated that compounds 5e and 5f could well fit into the dimer-dimer interface of HBV core protein dominated by hydrophobic interactions. Notably, their binding modes were different from the lead compound K284-1405, which may be attributed to the additional substituent groups in the quinazolinone scaffold. Taken together, 5e and 5f possessed novel chemical structure and potent anti-HBV activity against both drug sensitive and resistant HBV strains, thus warranting further research as potential non-nucleoside anti-HBV candidates.
|
Antiviral activity against HBV infected in human HepAD38 cells assessed as reduction in viral DNA levels incubated for 6 days by PCR analysis
|
Hepatitis B virus
|
11.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint.
Year : 2020
Volume : 63
Issue : 11
First Page : 6066
Last Page : 6089
Authors : Wang C, Pei Y, Wang L, Li S, Jiang C, Tan X, Dong Y, Xiang Y, Ma Y, Liu G.
Abstract : Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.
|
Antiviral activity against HBV infected in human HepG2.2.15 cells assessed as reduction in viral DNA levels incubated for 6 days by PCR analysis
|
Hepatitis B virus
|
0.0022
nM
|
|
Journal : J Med Chem
Title : Discovery of (1H-Pyrazolo[3,4-c]pyridin-5-yl)sulfonamide Analogues as Hepatitis B Virus Capsid Assembly Modulators by Conformation Constraint.
Year : 2020
Volume : 63
Issue : 11
First Page : 6066
Last Page : 6089
Authors : Wang C, Pei Y, Wang L, Li S, Jiang C, Tan X, Dong Y, Xiang Y, Ma Y, Liu G.
Abstract : Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 μM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.
|
Antiviral activity against wild type HBV infected in human HepG2 2.2.15 cells assessed as inhibition of viral DNA replication at 10 uM measured after incubation of 72 hrs by RT-PCR analysis relative to control
|
Hepatitis B virus
|
96.82
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents.
Year : 2021
Volume : 29
First Page : 115892
Last Page : 115892
Authors : Gu X,Zhang Y,Zou Y,Li X,Guan M,Zhou Q,Qiu J
Abstract : As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC values of 0.19 and 0.18 μM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π-π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.
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Antiviral activity against lamivudine/entecavir-resistant HBV rtL180M/rtM204V/rtT184L mutant infected in human HepG2 2.2.15 cells assessed as inhibition of viral DNA replication at 10 uM measured after incubation of 72 hrs by RT-PCR analysis relative to control
|
Hepatitis B virus
|
20.71
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of new phenyl acrylamide derivatives as potent non-nucleoside anti-HBV agents.
Year : 2021
Volume : 29
First Page : 115892
Last Page : 115892
Authors : Gu X,Zhang Y,Zou Y,Li X,Guan M,Zhou Q,Qiu J
Abstract : As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC values of 0.19 and 0.18 μM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π-π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.
|
Antiviral activity against Hepatitis B virus infected in human HePAD38 cells assessed as reduction in viral DNA replication incubated for 7 days by RT-PCR analysis
|
Hepatitis B virus
|
0.6
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery and structure activity relationship of glyoxamide derivatives as anti-hepatitis B virus agents.
Year : 2021
Volume : 31
First Page : 115952
Last Page : 115952
Authors : Amblard F,Boucle S,Bassit L,Chen Z,Sari O,Cox B,Verma K,Ozturk T,Ollinger-Russell O,Schinazi RF
Abstract : Chronic hepatitis B viral infection is a significant health problem world-wide, and currently available antiviral agents suppress HBV infections, but rarely cure this disease. It is presumed that antiviral agents that target the viral nuclear reservoir of transcriptionally active cccDNA may eliminate HBV infection. Through a series of chemical optimization, we identified a new series of glyoxamide derivatives affecting HBV nucleocapsid formation and cccDNA maintenance at low nanomolar levels. Among all the compounds synthesized, GLP-26 displays a major effect on HBV DNA, HBeAg secretion and cccDNA amplification. In addition, GLP-26 shows a promising pre-clinical profile and long-term effect on viral loads in a humanized mouse model.
|
Antiviral activity against Hepatitis B virus infected in human HepG2.2.15.7 assessed as reduction in HBV DNA level incubated for 9 days media replaced every 3 days once with test compound by RT-PCR analysis
|
Hepatitis B virus
|
0.18
nM
|
|
Journal : RSC Med Chem
Title : Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin
Year : 2020
Volume : 11
Issue : 5
First Page : 597
Last Page : 601
Authors : Samunuri, Ramakrishnamraju, Toyama, Masaaki, Pallaka, Renuka Sivasankar, Neeladri, Seshubabu, Jha, Ashok Kumar, Baba, Masanori, Bal, Chandralata
Abstract : Modified carbocyclic nucleosides (4a-g) constituting 7-deazapurine, 4'-methyl, exocyclic double bond and 2',3'-hydroxy were synthesized. NOE and X-ray studies of 4c confirmed the a-configuration of 4'-methyl. The anti-HBV assay demonstrated 4e (IC50 = 3.4 microM) without notable cytotoxicity (CC50 = 87.5 microM) as a promising lead for future exploration.
|
Antiviral activity against HBV infected in human HepG2.2.15 cells assessed as inhibition of DNA replication at 10 uM supplemented with fresh medium containing compound every 2 days for 6 days by RT-PCR analysis relative to control
|
Hepatitis B virus
|
96.9
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as potential anti-HBV and anti-HCC agents.
Year : 2020
Volume : 205
First Page : 112581
Last Page : 112581
Authors : Qiu J,Zhou Q,Zhang Y,Guan M,Li X,Zou Y,Huang X,Zhao Y,Chen W,Gu X
Abstract : As a continuation of earlier works, a series of novel quinazolinone derivatives (5a-s) were synthesized and evaluated for their in vitro anti-HBV and anti-hepatocellular carcinoma cell (HCC) activities. Among them, compounds 5j and 5k exhibited most potent inhibitory effect on HBV DNA replication in both drug sensitive and resistant (lamivudine and entecavir) HBV strains. Interestingly, besides the anti-HBV effect, compound 5k could significantly inhibit the proliferation of HepG2, HUH7 and SK- cells, with IC values of 5.44, 6.42 and 6.75 μM, respectively, indicating its potential anti-HCC activity. Notably, the in vitro anti-HCC activity of 5k were more potent than that of positive control 5-fluorouracil and sorafenib. Further studies revealed that compound 5k could induce HepG2 cells apoptosis by dose-dependently upregulating Bad and Bax expression and decreasing Bcl-2 and Bcl-xl protein level. Considering the potent anti-HBV and anti-HCC effect, compound 5k might be a promising lead to develop novel therapeutic agents towards HBV infection and HBV-induced HCC.
|
Antiviral activity against lamivudine and entecavir-resistant HBV harboring rtL180 M/rtM204V/rtT184L mutant infected in human HepG2.2.15 cells assessed as inhibition of DNA replication at 10 uM supplemented with fresh medium containing compound every 2 days for 6 days by RT-PCR analysis relative to control
|
Hepatitis B virus
|
18.92
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel quinazolinone derivatives as potential anti-HBV and anti-HCC agents.
Year : 2020
Volume : 205
First Page : 112581
Last Page : 112581
Authors : Qiu J,Zhou Q,Zhang Y,Guan M,Li X,Zou Y,Huang X,Zhao Y,Chen W,Gu X
Abstract : As a continuation of earlier works, a series of novel quinazolinone derivatives (5a-s) were synthesized and evaluated for their in vitro anti-HBV and anti-hepatocellular carcinoma cell (HCC) activities. Among them, compounds 5j and 5k exhibited most potent inhibitory effect on HBV DNA replication in both drug sensitive and resistant (lamivudine and entecavir) HBV strains. Interestingly, besides the anti-HBV effect, compound 5k could significantly inhibit the proliferation of HepG2, HUH7 and SK- cells, with IC values of 5.44, 6.42 and 6.75 μM, respectively, indicating its potential anti-HCC activity. Notably, the in vitro anti-HCC activity of 5k were more potent than that of positive control 5-fluorouracil and sorafenib. Further studies revealed that compound 5k could induce HepG2 cells apoptosis by dose-dependently upregulating Bad and Bax expression and decreasing Bcl-2 and Bcl-xl protein level. Considering the potent anti-HBV and anti-HCC effect, compound 5k might be a promising lead to develop novel therapeutic agents towards HBV infection and HBV-induced HCC.
