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

描述（由申请人提供）：美国每年约有1000人死于慢性肝病，其中40%的病例是由丙型肝炎病毒引起的。该病毒的基因组有一个正链RNA和一个高度容易出错的依赖NS5B RNA的RNA聚合酶，用于基因组复制。因此，丙型肝炎病毒迅速演变为6种基因型和超过14种亚基因型。在开发有效的直接作用抗病毒药物（DAA）方面已经做出了巨大的努力，然而，由于关注在西方国家最主要的基因型1a，我们忽视了大约30%的HCV感染者，此外，在第三世界国家发现的受害者。病毒的异质性明显限制了发现泛基因型DAA。话虽如此，我建议通过了解最不同的HCV NS3/4A蛋白酶在底物识别方面的差异，我们可以更接近设计一种满足两个主要特性的抑制剂：1)抑制剂必须适合所有HCV NS3/4A蛋白酶的整体底物包膜；2)抑制剂必须表现出非常低的耐药敏感性。为此，不同基因型的HCV NS3/4A的蛋白酶结构域的晶体结构将与它们的天然底物和抑制剂一起确定。

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.