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

• 批准号: 10218004
• 负责人: Jacques J. Kessl
• 金额: $ 35.55万
• 依托单位: UNIVERSITY OF SOUTHERN MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218004
• 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; Structure; Testing; Toxic effect; Viral; Virion; Virus Replication; base; cofactor; design; experimental study; high throughput screening; improved; inhibitor/antagonist; mutant; particle; pharmacophore; quinoline; scaffold; screening; small molecule inhibitor; therapeutic target; transcriptional coactivator p75; viral DNA; viral RNA; virology

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.

摘要 HIV-1整合酶（integrase，IN）是HIV-1病毒复制所必需的一个临床靶点。早期 在感染的步骤中，四聚体IN与两个病毒DNA末端结合，并催化它们整合到病毒DNA中。 寄主染色体已报道一类新的变构IN抑制剂（ALLINI）抑制酶， 通过促进异常的IN多聚化发挥作用。有趣的是，在受感染的细胞中， HIV-1复制的早期和晚期都受到损害。特别地，ALLINI处理的病毒体是 发现显示深刻的病毒核心形态缺陷类似于观察到的几个 复制缺陷型II类IN突变体。总的来说，这些研究表明，除了 除了已知的早期催化作用外，IN还在整个过程中起着重要的非催化作用。 HIV-1复制的晚期阶段。我们最近能够发现IN与几种病毒RNA结合 在一些实施方案中，ALLINI强烈地调节病毒体中的这些相互作用。另外我们 观察到IN可以将这些结合的vRNA元件聚集在一起，这表明IN在vRNA中可能起作用。 凝本申请将测试以下假设：IN-vRNA相互作用和IN-vRNA相互作用。 寡聚化对于感染性病毒体的正确形成都是至关重要的，可以通过 小分子抑制剂。在目标1中，我们将充分表征IN-vRNA复合物，并阐明IN-vRNA复合物的结构。 适当的IN多聚化对于vRNA结合和颗粒成熟的重要性。在目标2中，我们 将设计能够调节IN-vRNA结合和颗粒成熟的新IN抑制剂。 从这些研究中获得的机制和分子细节将指导未来的药物靶向 这些关键的非催化IN功能在病毒复制的后期启动。