Antiviral targeting to suppress drug resistance

抗病毒靶向抑制耐药性

• 批准号: 10513871
• 负责人: John Damon Chodera
• 金额: $ 213.26万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513871
• 关键词: Drug resistance; Structure

The last decades have emphasized the pandemic potential of the flaviviruses, picornaviruses and coronaviruses. Traditional drug discovery approaches for antiviral agents have generally focused on direct-acting inhibitors of viral targets, usually enzymes, that disrupt function and thus inhibit viral growth. However, the effectiveness of loss-of-function antivirals can be rapidly overcome by the outgrowth of drug-resistant variants. Multi-drug therapy is an effective solution to this problem that has been employed for HIV and hepatitis C viruses. Unfortunately, multi-drug therapy remains an expensive, long-term approach ill-suited to rapid response to new pandemic viruses and use in impoverished settings. To address this challenge in antiviral drug development, Project 1 will use a combination of genetic strategies and deep mutational analysis to identify specific viral proteins and small molecule targeting strategies with the aim of suppressing the selection of drug-resistant viral variants. We will focus on identifying proteins that have the potential, when bound to inhibitors, to be 'dominant disruptors' of viral RNA replication or virion function by producing or acting as 'molecular poisons' towards all developing viruses inside an infected cell. In this scenario, the drug-susceptible parent viruses can act as dominant killers of drugresistant variants, thus blocking the propagation of resistance. Our data have identified both viral proteases and capsid protein targets as having potential to induce dominant-disruptor phenotypes upon binding smallmolecules drugs. In addition, deep mutational scanning and biochemical methods will enable us to identify specific small-molecule binding sites on diverse viral targets that further avoid resistance by targeting locations at which mutations are not tolerated due to fitness cost. The combination of these approaches will yield both genetically validated viral targets, and particular regions of viral targets, that can suppress the formation of drug resistance as well as approaches for small-molecule targeting that are unlikely to allow the selection for resistance through classical mutational variation. These targets can then enter the consortium pipeline for rapid progression to screening, hit-to-lead development and validation in animal models of infection.

过去几十年强调了黄病毒、小核糖核酸病毒和冠状病毒的大流行潜力。 用于抗病毒剂的传统药物发现方法通常集中于直接作用的抗病毒药物抑制剂。 病毒靶点，通常是破坏功能从而抑制病毒生长的酶。然而， 丧失功能的抗病毒药物可以通过产生耐药变体而迅速克服。多药治疗 是一个有效的解决这个问题，已用于艾滋病毒和丙型肝炎病毒。不幸的是， 多种药物治疗仍然是一种昂贵的、长期的方法，不适合对新的大流行病作出快速反应 病毒和贫困地区的使用。为了解决抗病毒药物开发中的这一挑战，项目1将 使用遗传策略和深度突变分析的组合来识别特定的病毒蛋白质和小 分子靶向策略，目的是抑制耐药病毒变异体的选择。我们将 重点是识别蛋白质，当与抑制剂结合时，它们有可能成为病毒的“主要干扰物”。 RNA复制或病毒体通过产生或作为“分子毒药”对所有发育中的病毒发挥作用 在一个被感染的细胞里。在这种情况下，对药物敏感的亲本病毒可以作为耐药性药物的主要杀手。 变异，从而阻断抗性的传播。我们的数据已经确定了病毒蛋白酶和 衣壳蛋白靶点具有在结合小分子后诱导显性破坏表型的潜力 毒品此外，深度突变扫描和生物化学方法将使我们能够识别 不同病毒靶点上的特异性小分子结合位点，通过靶向位置进一步避免耐药性 由于适应度成本，在该值下突变是不被容忍的。这些方法的结合将产生 基因验证的病毒靶点，以及病毒靶点的特定区域，可以抑制药物的形成， 抗性以及小分子靶向方法不太可能允许选择 通过典型的突变变异产生抗性。然后，这些目标可以进入财团管道， 在动物感染模型中进行筛选、靶向开发和验证。