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综合（IN）是病毒生命周期开发新疗法的关键目标。尽管FDA批准的活跃部位抑制剂（如Raltegravir）成功开发了，但 Elvitegravir和Dolutegravir对这些试剂的抵抗威胁着他们的长期效用。变构在与LEDGF/p75位点结合的抑制剂中，代表了替代策略开发不会具有相同阻力概况的化合物。这些变构最近已显示抑制剂通过促进异常而影响活性多重化，这一过程仍未得到充分理解。据信与 CCD二聚体界面内的LEDGF/P75袋诱导了另一个招募然后能够在该位点结合的蛋白质，导致不活跃的高阶形成低聚物。当前的提案的重点是旨在证明的化合物的开发在CCD二聚体/CTD接口中，以更有效地“催化”此过程，从而导致抑制in。该提案的关键组成部分也是开发全新的脚手架能够结合到LEDGF/p75口袋，并预测显示出独特的阻力与先前合成的变构抑制剂相比。