In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061 - Structural analysis indicates different resistance mechanisms

被引：244

作者：

Lin, C ^{[1
]}

Lin, K ^{[1
]}

Luong, YP ^{[1
]}

Rao, BG ^{[1
]}

Wei, YY ^{[1
]}

Brennan, DL ^{[1
]}

Fulghum, JR ^{[1
]}

Hsiao, HM ^{[1
]}

Ma, S ^{[1
]}

Maxwell, JP ^{[1
]}

Cottrell, KM ^{[1
]}

Perni, RB ^{[1
]}

Gates, CA ^{[1
]}

Kwong, AD ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2004年 / 279卷 / 17期

关键词：

D O I：

10.1074/jbc.M313020200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We have used a structure-based drug design approach to identify small molecule inhibitors of the hepatitis C virus (HCV) NS3.4A protease as potential candidates for new anti-HCV therapies. VX-950 is a potent NS3.4A protease inhibitor that was recently selected as a clinical development candidate for hepatitis C treatment. In this report, we describe in vitro resistance studies using a subgenomic replicon system to compare VX-950 with another HCV NS3.4A protease inhibitor, BILN 2061, for which the Phase I clinical trial results were reported recently. Distinct drug-resistant substitutions of a single amino acid were identified in the HCV NS3 serine protease domain for both inhibitors. The resistance conferred by these mutations was confirmed by characterization of the mutant enzymes and replicon cells that contain the single amino acid substitutions. The major BILN 2061-resistant mutations at Asp(168) are fully susceptible to VX-950, and the dominant resistant mutation against VX-950 at Ala(156) remains sensitive to BILN 2061. Modeling analysis suggests that there are different mechanisms of resistance to VX-950 and BILN 2061.

引用

页码：17508 / 17514

页数：7

共 40 条

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