Novel anti-HIV compounds targeting the HIV-1 matrix protein

针对 HIV-1 基质蛋白的新型抗 HIV 化合物

• 批准号: 9926276
• 负责人: Simon Cocklin
• 金额: $ 55.51万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926276
• 关键词: Affect; Affinity; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Antiviral Therapy; Binding; Binding Sites; Biological Assay; Biology; Chemicals; Clinical; Complex; Computer Assisted; Data; Drug Design; Drug resistance; Evaluation; Exhibits; Generations; Genetic; Glycoproteins; Goals; HIV; HIV-1; Infection; Investigation; Kinetics; Lead; Learning; Ligands; Light; Link; Measures; Mediating; Methods; Molecular; Molecular Probes; Mutation; N-terminal; Nuclear Magnetic Resonance; Nucleic Acid Binding; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphatidylinositols; Process; Property; Proteins; Reagent; Regimen; Resistance; Resolution; Role; Site; Specificity; Structure; Surface Plasmon Resonance; Techniques; Testing; Therapeutic; Therapeutic Index; Toxic effect; Viral; Virion; Virus; Virus Assembly; Virus Replication; analog; base; clinical candidate; clinically relevant; combat; cytotoxic; design; gag Gene Products; improved; inhibitor/antagonist; insight; lead optimization; matrix protein, Human immunodeficiency virus type 1; mutant; next generation; novel; novel strategies; novel therapeutics; particle; resistant strain; scaffold; screening; small molecule; small molecule inhibitor; success; tool; virtual screening

ABSTRACT Because of the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The HIV-1 matrix protein (MA) is an essential viral component with established roles in the assembly of the virus. Using a combination of virtual screening, surface plasmon resonance analysis, and antiviral testing, we were the first to identify small drug- like molecules that bind to the HIV-1 MA protein and that possess broad-range anti-HIV properties. Combining computer-aided drug design techniques and medicinal chemistry, we have designed and synthesized next generation compounds that interact with HIV-1 MA and inhibit the virus. Our current lead compound, MTI-14 binds to HIV-1 MA (as judged by SPR and NMR), has low toxicity, and has mid-micromolar potency. Moreover, MA mutant viruses display reduced sensitivity to MTI-14, demonstrating that the antiviral action of the compound is mediated through disruption of the functions of MA. Excitingly, preliminary mechanism-of-action studies also suggest that MTI-14 functions by blocking HIV-1 Env incorporation into new viral particles. We propose to further optimize this MA-targeted inhibitory compound to potencies that are clinically relevant, while using these inhibitors as molecular tools to dissect the biology of the MA protein in the HIV-1 replication cycle. The goals of the proposed studies will be accomplished by three discrete but highly integrated specific aims. In Aim 1, the leads will be optimized through structure-guided design and medicinal chemistry approaches, their kinetic properties including on- and off-rates and binding affinities (KD) will be measured, and their binding site verified by chemical shift NMR and competitive fluorescent polarization assays. In addition, novel chemotypes will be sought using ligand-based screening approaches. In Aim 2, the antiviral potency and breadth of the leads will be assessed. Evaluation of their toxicity will be performed in parallel. In Aim 3, we will perform detailed mechanism-of-action studies, generate resistance mutants, and determine the structures of the new inhibitors in complex with MA using crystallographic and nuclear magnetic resonance methods. The data from these studies will be used in designing potent next-generation MA-targeted inhibitors with high genetic barriers and unique modes of action. Such compounds will also serve as novel molecular probes for HIV-1 MA functions.

摘要 由于耐药菌株的出现以及与当前药物相关的累积毒性， 尽管目前的抗HIV药物治疗中，仍需要新的HIV-1复制抑制剂。HIV-1基质蛋白（MA）是一种 在病毒装配中具有确定作用的基本病毒组分。结合使用虚拟 筛选，表面等离子体共振分析，和抗病毒测试，我们是第一个确定小药物- 例如与HIV-1 MA蛋白结合并具有广泛抗HIV特性的分子。结合 计算机辅助药物设计技术和药物化学，我们已经设计和合成下一步 产生与HIV-1 MA相互作用并抑制病毒的化合物。我们目前的先导化合物MTI-14 与HIV-1 MA结合（通过SPR和NMR判断），具有低毒性，并具有中等微摩尔效力。此外，委员会认为， MA突变体病毒显示出对MTI-14的敏感性降低，表明MA突变体病毒的抗病毒作用与MTI-14无关。 化合物通过破坏MA的功能来介导。令人兴奋的是，初步的作用机制 研究还表明MTI-14通过阻断HIV-1 Env掺入到新的病毒颗粒中而起作用。我们 建议进一步优化这种MA靶向抑制化合物，使其具有临床相关的效力， 利用这些抑制剂作为分子工具来剖析HIV-1复制周期中MA蛋白的生物学。 拟议研究的目标将通过三个独立但高度综合的具体目标来实现。在 目的1，通过结构导向设计和药物化学方法优化先导化合物， 将测量动力学性质，包括结合速率和解离速率以及结合亲和力（KD），并且将测量它们的结合位点 通过化学位移NMR和竞争性荧光偏振测定验证。此外，新的化学型 将使用基于配体的筛选方法来寻求。在目标2中， 将对线索进行评估。将平行进行其毒性评价。在目标3中，我们将 详细的作用机制研究，产生抗性突变体，并确定新的结构 使用晶体学和核磁共振方法研究与MA复合的抑制剂。的数据 这些研究将用于设计具有高遗传屏障的有效的下一代MA靶向抑制剂 和独特的行动模式。这些化合物也将作为HIV-1 MA的新型分子探针 功能协调发展的