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Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine,a Nonnucleoside Reverse Transcriptase Inhibitor 下载免费PDF全文
P. Fletcher S. Harman H. Azijn N. Armanasco P. Manlow D. Perumal M.-P. de Bethune J. Nuttall J. Romano R. Shattock 《Antimicrobial agents and chemotherapy》2009,53(2):487-495
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Anne-Genevieve Marcelin Philippe Flandre Diane Descamps Laurence Morand-Joubert Charlotte Charpentier Jacques Izopet Mary-Anne Trabaud Henia Saoudin Constance Delaugerre Catherine Tamalet Jacqueline Cottalorda Magali Bouvier-Alias Dominique Bettinger Georges Dos Santos Annick Ruffault Chakib Alloui Cecile Henquell Sylvie Rogez Francis Barin Anne Signori-Schmuck Sophie Vallet Bernard Masquelier Vincent Calvez and the ANRS AC Resistance Study Group 《Antimicrobial agents and chemotherapy》2010,54(1):72-77
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Christian Voitenleitner Renae Crosby Jill Walker Katja Remlinger Jessica Vamathevan Amy Wang Shihyun You John Johnson III Ermias Woldu Stephanie Van Horn Joseph Horton Katrina Creech J. Brad Shotwell Zhi Hong Robert Hamatake 《Antimicrobial agents and chemotherapy》2013,57(11):5216-5224
GSK2485852 (referred to here as GSK5852) is a hepatitis C virus (HCV) NS5B polymerase inhibitor with 50% effective concentrations (EC50s) in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged in these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H. Testing of a diverse mutant panel also revealed a lack of cross-resistance against known resistance mutations in other viral proteins. Data from both the newer 454 sequencing method and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA-dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long-term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes, but its superior resistance profile suggests that it could be an attractive component of an all-oral regimen for treating HCV. 相似文献
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Warren Kati Gennadiy Koev Michelle Irvin Jill Beyer Yaya Liu Preethi Krishnan Thomas Reisch Rubina Mondal Rolf Wagner Akhteruzzaman Molla Clarence Maring Christine Collins 《Antimicrobial agents and chemotherapy》2015,59(3):1505-1511
Dasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50 resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections. 相似文献
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