Structure-based design of robust cross-genotypic NS3/4A protease inhibitors that avoid resistance

基于结构的稳健跨基因型 NS3/4A 蛋白酶抑制剂的设计，可避免耐药性

基本信息

批准号：
9249924
负责人：
Ashley Nicole Matthew
金额：
$ 3.12万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249924
关键词：
Active Sites Affect Antiviral Agents Area Binding Biological Assay Chemistry Chronic Hepatitis Cleaved cell Comprehension Computational Technique Crystallization Dimensions Drug Design Drug resistance Electrostatics Enzyme Inhibition Exhibits Genetic Variation Genotype Hepatitis C Laboratories Liver Cirrhosis Methods Modeling Molecular Mutation Peptide Hydrolases Pharmaceutical Preparations Physicians Polyproteins Predisposition Primary carcinoma of the liver cells Protease Inhibitor Proteins Resistance Scientist Sequence Homology Site Structure Supervision Techniques Testing Therapeutic Training Treatment outcome Triad Acrylic Resin Variant Viral Viral Proteins Virus base clinical development design effective therapy experience improved inhibitor/antagonist insight novel novel therapeutics pathogen public health relevance resistance mechanism therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV), a pathogen that infects over 150 million people worldwide, is the leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV is a genetically diverse virus with 6 known genotypes with genotypes 1 and 3 being the most prevalent. This genetic diversity makes HCV infection difficult to treat. In the last few years, the advent of direct-acting antivirals (DAAs) has remarkably improved therapeutic options and treatment outcomes. However, despite highly potent inhibitors against multiple proteins, drug resistance is a major problem in all drug classes. Drug resistance is a loss of inhibitor potency while maintaining substrate processing. Though NS3/4A protease inhibitors are highly potent, they are not efficacious against all genotypes and are susceptible to drug resistance. Underlying differential inhibitor potency are the molecular mechanisms of drug resistance and genotypic differences. Elucidating these are key to developing protease inhibitors that avoid drug resistance and are effective against all HCV genotypes. Specifically most protease inhibitors in clinical development contain P2 moieties that contact unessential residues of the protease, which while increasing potency also increases their susceptibility to single site mutations that confer drug resistance. I hypothesize that protease inhibitors that avoid contact with these residues while leveraging contact with unexploited areas in the active site will result in inhibitors with enhanced potency and higher barriers to drug resistance. To investigate this hypothesis, using computational techniques, I will design a panel of novel protease inhibitors with extended P4 groups. I will then synthesize and enzymatically assay these protease inhibitors. Top leads will be co-crystalized with the protease and structurally analyzed to optimize the computational designs and initiate iterative rounds of inhibitor design. This project will provide molecular insights about the mechanisms of drug resistance as well as new strategies for the design of novel protease inhibitors for the effective treatment of HCV infection.

描述（由适用提供）：丙型肝炎病毒（HCV）是全球感染超过1.5亿人的病原体，是慢性肝炎，肝硬化和肝细胞癌的主要原因。 HCV是一种遗传多样的病毒，具有6种已知基因型，基因型1和3是最普遍的。这种遗传多样性使HCV感染难以治疗。在过去的几年中，直接作用抗病毒药（DAAS）的进步已得到明显改善的治疗选择和治疗结果。然而，尽管对多种蛋白质有高度有效的抑制剂，但在所有药物类别中，耐药性是一个主要问题。耐药性是抑制剂效力的损失，同时维持底物处理。尽管NS3/4A蛋白抑制剂具有很高的潜力，但对所有基因型并不有效，并且容易受到影响耐药性。潜在的差异抑制剂效力是耐药性和基因型差异的分子机制。阐明这些是发展蛋白质抑制剂的关键，从而避免耐药性并有效抵抗所有HCV基因型。特别是临床发育中的大多数蛋白质抑制剂都包含P2部分接触蛋白质的不必要耐药性的P2部分，同时增加了效力，还增加了其对赋予耐药性的单个部位突变的敏感性。我假设避免与这些抗性接触的蛋白酶抑制剂，同时利用与活性部位中意外区域接触的蛋白酶抑制剂将导致抑制剂具有增强的效力和耐药性较高的障碍。为了研究这一假设，使用计算技术，我将设计一个具有扩展P4组的新型蛋白酶抑制剂。然后，我将合成并酶法测定这些蛋白酶抑制剂。顶级铅将与蛋白酶共结晶，并在结构上进行分析，以优化计算设计并启动抑制剂设计的迭代回合。该项目将提供有关耐药性机制以及设计新型蛋白酶抑制剂的新策略的分子见解，以有效治疗HCV感染。