Multimeric HIV-1 Integrase Inhibitors

多聚体 HIV-1 整合酶抑制剂

• 批准号: 10570935
• 负责人: Mamuka Kvaratskhelia
• 金额: $ 49.82万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570935
• 关键词: Architecture; Binding; Biochemical; C-terminal; Capsid; Catalytic Domain; Clinic; Clinical; Collaborations; Complex; Cryoelectron Microscopy; Development; Drug Industry; Evolution; Exhibits; Funding; Future; Generations; Genetic; Genetic Enhancement; Genome; Goals; HIV; HIV-1; HIV-1 integrase; Head; Healthcare; Highly Active Antiretroviral Therapy; Impairment; In Vitro; Integrase; Integrase Inhibitors; International; Lead; Length; Letters; Medicine; Modification; Molecular Biology; Mutation; Phenotype; Positioning Attribute; Productivity; Publications; RNA; RNA Binding; Research; Resistance; Ribonucleoproteins; Seminal; Shapes; Solid; Structure; Terminal Disease; Testing; Time; Translating; Variant; Viral; Viral Physiology; Virion; Virus; Virus Replication; Work; chronic infection; clinical development; clinically relevant; dimer; drug resistance development; drug resistant virus; experimental study; inhibitor; innovation; mutant; novel; novel therapeutics; particle; preference; protein aggregation; pyridine; quinoline; rational design; resistant strain; response; synergism; therapeutic target; tool; transcriptional coactivator p75; viral RNA; virology

Abstract The overarching goals of the present proposal are to develop first-in-class multimeric HIV-1 integrase (IN) inhibitors (MINIs) for their future clinical development and to exploit these compounds as powerful investigational tools for HIV-1 molecular biology to uncover critical molecular interactions during maturation. Because of their unique mode of action, MINIs are expected to potently inhibit all drug resistant viral phenotypes in the clinic, which continually evolve in response to currently used ARTs. By rationally modifying archetypal, multifunctional quinoline-based allosteric IN inhibitors (ALLINIs), we have developed highly potent pyridine-based MINIs, which are highly selective for inducing hyper-multimerization of IN. Our SAR studies have been critical for understanding the antiviral mode of action of these inhibitors and allowed us to clearly delineate the significance of HIV-1 IN multimerization as a novel, attractive therapeutic target. We have shown this hyper-multimerization of IN occurs in viral particles during maturation, which in turn impairs IN binding to the viral RNA genome and results in eccentric, non-infectious virions with ribonucleoprotein complexes being displaced outside of the protective capsid core. In addition, our rational design approach enabled us to develop a lead compound, MINI KF116, with a markedly enhanced genetic barrier to resistance compared with its ALLINI counterparts. In particular, KF116 is fully active against the HIV-1 variant with an A128T IN substitution, which confers resistance to the majority of archetypal ALLINIs. Instead, triple (T124N/V165I/T174I) IN substitutions, which significantly compromise viral replication even with a compensatory V165I mutation, are necessary to confer resistance to KF116. Collectively, our findings argue that pyridine-based KF116 is as an excellent platform for the development of second generation MINIs. Our future work will extend these studies and build on our exciting new preliminary results, which show that MINIs/ALLINIs exhibit striking preference for full-length wild type IN tetramers. Specifically, we found that inhibitor binding to the catalytic core domain (CCD) dimer is not sufficient for its activity and that the CCD-inhibitor-C-terminal domain interactions between adjoining full-length IN tetramers are necessary to induce hyper-multimerization of IN. Accordingly, we propose to dissect unique structural features of IN tetramers as authentic targets for MINIs and ALLINIs (aim 1) and utilize this information to optimize second generation inhibitors for their future clinical development (aim 2). The proposed studies are highly complementary to and will synergize with very active ongoing efforts in the pharmaceutical industry to translate the first-in-class MINIs/ALLINIs into the clinic with the ultimate goal of delivering safer next generation therapeutics.

摘要 本提案的总体目标是开发一流的多聚体HIV-1整合酶（IN） 抑制剂（MINI）的未来临床开发，并利用这些化合物作为强大的研究 HIV-1分子生物学的工具，以揭示成熟过程中的关键分子相互作用。因为他们的 独特的作用模式，MINI有望在临床上有效抑制所有耐药病毒表型， 其响应于当前使用的ART而不断发展。通过合理修改原型，多功能 基于喹啉的变构IN抑制剂（ALLINI），我们已经开发了高效的基于吡啶的MINI， 对诱导IN的超多聚化具有高度选择性。我们的SAR研究对于 了解这些抑制剂的抗病毒作用模式，并使我们能够清楚地描述其意义， HIV-1 IN多聚化作为一个新的，有吸引力的治疗靶点。我们已经证明了这种超多聚化 在成熟过程中，IN在病毒颗粒中发生，这反过来又损害IN与病毒RNA基因组的结合， 导致具有核糖核蛋白复合物的偏心的、非感染性的病毒体被移位到 保护性衣壳核心。此外，我们合理的设计方法使我们能够开发出一种先导化合物，MINI KF 116，与其ALLINI对应物相比，具有显著增强的抗性遗传屏障。在 特别地，KF 116对具有A128 T IN取代的HIV-1变体具有完全活性，这赋予了抗性 对大多数典型的阿利尼人来说。相反，三重（T124 N/V165 I/T174 I）IN取代，其显著地 即使具有补偿性V165 I突变，也会损害病毒复制， KF116总的来说，我们的研究结果表明，基于吡啶的KF 116是一个很好的开发平台。 第二代MINI我们未来的工作将扩展这些研究，并建立在我们令人兴奋的新的初步研究基础上。 结果显示MINI/ALLINI对全长野生型IN四聚体表现出显著的偏好。 具体地说，我们发现抑制剂与催化核心结构域（CCD）二聚体的结合不足以发挥其活性 并且相邻全长IN四聚体之间的CCD-抑制剂-C-末端结构域相互作用是 这是诱导IN过度多聚化所必需的。因此，我们建议剖析独特的结构特征， IN四聚体作为MINI和ALLINI的真实靶标（目的1），并利用此信息优化第二个 用于其未来临床开发的抑制剂（目的2）。研究建议高度 补充，并将协同非常积极的正在进行的努力，在制药行业， 一流的MINI/ALLINI进入临床，最终目标是提供更安全的下一代产品 治疗学