New Inhibitors Targeting HIV-1 Integrase During Viral Maturation

在病毒成熟过程中针对 HIV-1 整合酶的新型抑制剂

基本信息

批准号：
10452601
负责人：
Jacques J. Kessl
金额：
$ 35.53万
依托单位：
UNIVERSITY OF SOUTHERN MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-08 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452601
关键词：
Affect Affinity Amino Acids Anti-Retroviral Agents Antiviral Agents Atomic Force Microscopy Binding Binding Sites Biochemical Biological Assay Biology Capsid Cells Chemicals Chromosomes Clinical Communities Complex Data Defect Development Drug Targeting Electrons Elements Enzymes Foundations Future Generations Genetic Genome HIV HIV-1 HIV-1 integrase Impairment In Vitro Infection Integrase Integrase Inhibitors Libraries Maps Mass Spectrum Analysis Membrane Molecular Morphogenesis Morphology Nucleosome Core Particle Patients Pharmaceutical Chemistry Phenotype Physical condensation Play Publishing RNA Binding Recombinants Reporting Research Institute Resistance Ribonucleoproteins Role Testing Toxic effect Viral Virion Virus Replication base cofactor design experimental study high throughput screening improved inhibitor mutant particle pharmacophore quinoline scaffold screening small molecule inhibitor therapeutic target transcriptional coactivator p75 viral DNA viral RNA virology

项目摘要

Abstract HIV-1 integrase (IN) is validated clinical target and is essential for viral replication. During the early steps of infection, tetrameric IN associates with two viral DNA ends and catalyzes their integration into the host chromosome. A new class of allosteric IN inhibitors (ALLINIs) has been reported to inhibit enzyme function by promoting aberrant IN multimerization. Interestingly, in infected cells these compounds impaired both early and late stages of HIV-1 replication. In particular, the ALLINI-treated virions were found to display profound viral core morphologies defects similar to those observed with several replication-defective class II IN mutants. Collectively, these studies have suggested that in addition to its known catalytic function in early stage, IN also plays an essential and non-catalytic role during the late stage of HIV-1 replication. We were recently able to discover that IN binds to several viral RNA (vRNA) elements and that ALLINIs strongly modulate these interactions in the virion. In addition, we observed that IN can bring these bound vRNA elements together suggesting a possible role in vRNA condensation. The present application will test the following hypothesis: IN-vRNA interactions and IN oligomerization which are both critical for the correct formation of infectious virions can be targeted by small molecule inhibitors. In aims 1, we will fully characterize the IN-vRNA complex and elucidate the significance of the proper IN multimerization for vRNA binding and particle maturation. In aims 2, we will design new IN inhibitors capable of modulating IN-vRNA binding and particle maturation. Mechanistic and molecular details that will emerge from these studies will guide future drug targeting initiatives of these critical non-catalytic IN functions in late stage of the viral replication.

抽象的 HIV-1积分酶（IN）是验证的临床靶标，对于病毒复制至关重要。在早期感染步骤，与两个病毒DNA末端的联合中的四聚体，并将其整合到宿主染色体。据报道，一类新的变构抑制剂（Allinis）抑制酶通过促进多聚化的异常来功能。有趣的是，在受感染的细胞中这些化合物 HIV-1复制的早期和晚期受损。特别是，经过同种处理的病毒粒子是发现显示出深刻的病毒核形态缺陷，类似于几个观察到的缺陷突变体中的复制缺陷II类。总的来说，这些研究表明，除了它在早期阶段已知的催化功能也起着必不可少的和非催化作用 HIV-1复制的后期。我们最近能够发现与几个病毒RNA结合（vrna）元素，并且allinis在病毒素中强烈调节了这些相互作用。另外，我们观察到可以将这些结合的vrna元素聚集在一起，这表明在VRNA中可能起作用缩合。本应用将检验以下假设：vRNA相互作用和对于正确形成感染性病毒而言至关重要的寡聚化可以由小分子抑制剂。在AIMS 1中，我们将充分表征vRNA络合物并阐明适当在多聚化中的重要性在VRNA结合和粒子成熟的情况下。在目标2中，我们将设计能够调节VRNA结合和颗粒成熟的抑制剂中的新抑制剂。这些研究将出现的机械和分子细节将指导未来的药物靶向这些关键的非催化性在病毒复制的后期功能的倡议。