HCV protease: from atomic mechanism for drug resistance to novel drug design

描述(申请人提供)：慢性肝病每年在美国造成约1000人死亡，40%的病例是由丙型肝炎病毒引起的。这种病毒有一个正链RNA作为其基因组，以及一个高度容易出错的NS5B依赖RNA的RNA聚合酶来进行基因组复制。结果，丙型肝炎病毒迅速进化出六种基因类型和超过14种亚型。人们已经努力开发有效的直接作用抗病毒药物(DAA)，然而，通过关注西方国家最主要的1a基因型，我们忽视了大约30%的丙型肝炎病毒感染者，而且在第三世界国家发现的受害者。该病毒的异质性明显限制了泛基因型DAA的发现。尽管如此，我建议通过了解最具差异性的丙型肝炎病毒NS3/4A蛋白酶底物识别的差异，我们可以更进一步地设计满足两个主要特性的抑制剂：1)抑制剂必须符合所有丙型肝炎病毒NS3/4A蛋白酶的底物包膜；2)抑制剂必须表现出非常低的耐药性敏感性。为此，将在与其天然底物和抑制物的络合物中确定来自不同基因型的丙型肝炎病毒NS3/4A的蛋白酶域的晶体结构。

DESCRIPTION (provided by applicant): Chronic liver disease kills an estimated 1000 people in the US every year and is caused in 40 percent of cases, by the hepatitis C virus. This virus has a positive strand RNA as its genome and a highly error prone NS5B RNA-dependent RNA polymerase for genomic replication. As a consequence, HCV has rapidly evolved with six genotypes and more than 14 sub-genotypes. Great efforts have been made to develop effective direct acting antivirals (DAA), however, by focusing on genotype 1a, the most predominant in western countries, we have neglected about 30 percent of people infected with HCV and moreover, victims found in third world countries. The heterogeneity of the virus has clearly set limitations to the discovery of a pan-genotypic DAA. That being said, I propose that by understanding the differences in substrate recognition of the most divergent HCV NS3/4A protease, we can get one step closer to designing an inhibitor that satisfies two major properties: 1) the inhibitor must fit within the overall substrate envelope of all HCV NS3/4A protease; 2) the inhibitor must exhibit a very low susceptibility to drug resistance. To that end, crystal structures of the protease domain of HCV NS3/4A from various genotypes will be determined in complex with their natural substrates and inhibitors.