Development of Novel Scaffolds as Tools for Allosteric HIV-1 Integrase Inhibition

开发新型支架作为变构 HIV-1 整合酶抑制工具

基本信息

批准号：
9765163
负责人：
JAMES R FUCHS
金额：
$ 23.4万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-16 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765163
关键词：
AIDS/HIV problem Acetic Acids Active Sites Address Affect Binding Binding Sites C-terminal Capsid Catalytic Domain Cell Culture Techniques Cells Chromosomes Clinical Complex Crystallization Data Development Disease Drug Design Evolution FDA approved Generations Genome Geometry Goals HIV HIV Integrase HIV therapy Hydrogen Bonding Indoles Industrialization Integrase Integrase Inhibitors Laboratories Lead Life Cycle Stages Ligands Minor Modification Patients Pharmaceutical Preparations Phenotype Play Process Proteins Resistance Resistance profile Role Series Side Site Structure Surface Therapeutic Thiophenes Translating United States Viral Viral Genome Virion Virus Integration Virus Replication analog antiretroviral therapy base bench to bedside cofactor design dimer improved inhibitor/antagonist novel novel therapeutics pressure public health relevance pyridine quinoline recruit resistance mutation scaffold screening success targeted treatment tool transcriptional coactivator p75 viral RNA viral resistance

项目摘要

Abstract HIV-1 integrase (IN) is a key target in the viral life cycle for the development of new therapeutics. Despite the successful development of FDA approved active site inhibitors like raltegravir, elvitegravir, and dolutegravir, resistance to these agents threatens their long-term utility. Allosteric IN inhibitors that bind at the LEDGF/p75 site of IN represent an alternative strategy for the development of compounds that will not share the same resistance profile. These allosteric inhibitors have recently been shown to affect IN activity through promotion of aberrant multimerization, a process that is still not well understood. It is believed that binding to the LEDGF/p75 pocket within the CCD dimer interface of IN induces the recruitment of another IN protein that then is able to bind at this site, resulting in the formation of an inactive higher order oligomer. The current proposal is focused on the development of compounds designed to probe the IN CCD dimer/CTD interface in an effort to more efficiently “catalyze” this process, leading to the inhibition of IN. A key component of this proposal is also the development of a completely new scaffold capable of binding to the LEDGF/p75 pocket and predicted to show a unique resistance profile compared to previously synthesized allosteric inhibitors.

抽象的 HIV-1 整合酶 (IN) 是病毒生命周期中用于开发新疗法的关键靶标。尽管 FDA 批准的活性位点抑制剂（如拉替拉韦）已成功开发，埃替拉韦和多替拉韦，对这些药物的耐药性威胁到它们的长期效用。与 IN LEDGF/p75 位点结合的 IN 抑制剂代表了一种替代策略开发不具有相同耐药性的化合物。最近已证明抑制剂可通过促进异常的 IN 活性来影响 IN 活性。多聚化，这一过程尚未被充分理解。 IN CCD 二聚体界面内的 LEDGF/p75 口袋诱导另一个 IN 的募集然后能够在该位点结合的蛋白质，导致形成无活性的高阶目前的提案重点是开发旨在探测的化合物。 IN CCD二聚体/CTD接口旨在更有效地“催化”这一过程，从而导致该提案的一个关键组成部分也是开发一种全新的药物。能够结合 LEDGF/p75 口袋的支架，预计会表现出独特的抗性与之前合成的变构抑制剂相比。