Drug Resistance in HCV NS3/4A - Inhibitor binding versus substrate recognition

 描述（由申请人提供）：HCVNS 3/4A及以上的耐药性-抑制剂结合对底物识别在过去的3-5年中，丙型肝炎病毒（HCV）的治疗已经通过直接作用的抗病毒药物（DAA）而发生了革命性的变化. NS 3/4A蛋白酶是开发DAA的HCV的第一个靶标。NS 3/4A蛋白酶抑制剂（PI）仍然是开发治疗选择的关键组成部分，包括目前处于III期临床试验中的联合治疗。虽然目前的PI对wil型基因型1 HCV非常有效，但HCV的快速演变和世界各地的基因型差异允许具有通常多个突变的可行变体对这些PI具有抗性，并降低其有效性。耐药性是由分子识别事件平衡的变化引起的，其选择性地削弱抑制剂结合，但维持治疗靶标的生物学功能。破坏治疗靶点的活性是必要的，但不足以避免耐药性。我们假设在PI治疗的压力下或在不同基因型中选择的多个突变的影响不是简单的加和，而是这些突变具有相互依赖的影响，引起结构和动态变化以赋予耐药性。我们将阐明HCV NS 3/4A耐药发生的分子机制，并开发和实施策略，设计新的抑制剂不易耐药。一个关键的策略是比较抑制剂结合底物识别，并避免功能上不必要的接触，容易耐药突变。我们开发的设计对耐药性不敏感的强效抑制剂的策略也将被翻译为黄病毒蛋白酶，如登革热，目前没有DAA或疫苗存在。

 DESCRIPTION (provided by applicant): Drug Resistance in HCV NS3/4A and Beyond - Inhibitor Binding versus Substrate Recognition In the last 3-5 years the treatment of Hepatitis C Virus (HCV) has been revolutionize by direct- acting antivirals (DAAs). NS3/4A protease was the first target for HCV where DAAs were developed. NS3/4A protease inhibitors (PIs) continue to be key components in the development of therapeutic options including combination therapies currently in phase 3 clinical trials. While the current PIs are highly potent against wil-type genotype 1 HCV, the rapid evolution of HCV and genotypic differences around the world allow viable variants with often multiple mutations that are resistant against these PIs, and decrease their effectiveness. Drug resistance is caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the therapeutic target. Disrupting the therapeutic target's activity is necessary but nt sufficient for avoiding resistance. We hypothesize that the impact of multiple mutations selected under the pressure of PI therapy or in different genotypes is not simply additive, but these mutations have interdependent effects causing structural and dynamic changes to confer resistance. We will elucidate the molecular mechanisms by which resistance occurs in HCV NS3/4A, and develop and implement strategies to design new inhibitors less susceptible to resistance. One key strategy is to compare inhibitor binding to substrate recognition and avoid functionally unessential contacts that are vulnerable to resistance mutations. The strategies we develop to design potent inhibitors less susceptible to resistance will also be translated to flaviviral proteases such as dengue, where no current DAA or vaccine exists.