Impact of Naturally Occurring Variants of HCV Protease on the Binding of Different Classes of Protease Inhibitors
详细信息 查看全文
- 作者：Xiao Tong ; Zhuyan Guo ; Jacquelyn Wright-Minogue ; Ellen Xia ; Andrew Prongay ; Vincent Madison ; Ping Qiu ; Srikanth Venkatraman ; Francisco Velazquez ; F. George Njoroge ; and Bruce A. Malcolm
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：February 7, 2006
- 年：2006
- 卷：45
- 期：5
- 页码：1353 - 1361
- 全文大小：481K
- 年卷期：v.45,no.5(February 7, 2006)
- ISSN：1520-4995
文摘
HCV drug discovery efforts have largely focused on genotype 1 virus due to its prevalenceand relatively poor response to current therapy. However, patients infected with genotype 2 and 3 virusesaccount for a significant number of cases and would also benefit from new therapies. In vitro studiesusing two chemically distinct protease inhibitors with clinical potential showed that one, VX-950, wasequally active on proteases from all three genotypes, whereas the other, BILN 2061, was significantlyless active on genotype 2 and 3 proteases. Naturally occurring variation near the inhibitor binding sitewas identified based on sequence alignment of the protease region from genotype 1-3 sequences.Substitution of amino acids in genotype 1 based on genotype 2 and 3 has revealed residues which impactbinding of BILN 2061. Substitution of residues 78-80, together with 122 and 132, accounted for mostof the reduced sensitivity of genotype 2. The most critical position affecting inhibitor binding to genotype3 protease was 168. Substitution of residues at positions 168, 123, and 132 fully accounted for the reducedsensitivity of genotype 3. Comparative studies of BILN 2061 and a closely related nonmacrocycle inhibitorsuggested that the rigidity of BILN 2061, while conferring greater potency against genotype 1, renderedit more sensitive to variations near the binding site. Free energy perturbation analysis confirmed theexperimental observations. The identification of naturally occurring variations which can affect inhibitorbinding is an important step in the design of broad-spectrum, second generation protease inhibitors.