Rational Design of antivrials targeted to HIV-1 capsid

针对 HIV-1 衣壳的抗病毒药物的合理设计

• 批准号: 7923533
• 负责人: Asim K Debnath
• 金额: $ 10万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2010-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923533
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Affinity; Anti-Retroviral Agents; Antiviral Agents; Area; Binding; Binding Sites; Biochemical; Biological Assay; C-terminal; Capsid; Capsid Proteins; Cell Culture Techniques; Cells; Clinical Trials; Combined Modality Therapy; Complement; Complex; Computer-Aided Design; Crystallography; Data; Databases; Development; Dimerization; Docking; Drug Delivery Systems; Drug resistance; Failure; Goals; HIV; HIV-1; HIV-1 drug resistance; HIV-1 vaccine; Highly Active Antiretroviral Therapy; In Vitro; Infection; Inhibitory Concentration 50; Laboratories; Lead; Libraries; Maps; Modeling; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Mutation Analysis; Nuclear Magnetic Resonance; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Prevention; Principal Investigator; Publishing; Reporting; Resolution; Role; Screening procedure; Site; Solutions; Structure; Techniques; Testing; Variant; Viral; Virion; Virus; Virus Assembly; Virus-like particle; Zinc; base; chemotherapy; cytotoxicity; design; dimer; gag Gene Products; indexing; inhibitor/antagonist; microbicide; monomer; mortality; novel; prevent; process optimization; programs; public health relevance; research study; small molecule; therapeutic target; virtual

DESCRIPTION (provided by applicant): The introduction of highly active antiretroviral therapy (HAART) has significantly decreased the morbidity and mortality among HIV-1 infected people. However, the development of drug resistance poses a serious threat to the treatment options available to patients. Furthermore, recent reports of failure in clinical trials of Merck HIV-1 vaccines and several microbicides reinforce the critical need to identify and develop new targets for anti-HIV-1 drugs. Novel drugs will broaden the scope of combination therapy and will help in reducing development of drug-resistant HIV-1 variants. The capsid domain of the HIV-1 Gag polyprotein plays a critical role in virus assembly and maturation and therefore represents an important potential target for developing drugs for AIDS therapy. We propose to develop novel anti-HIV-1 agents targeted to a highly conserved hydrophobic pocket and to the dimerization interface in the C-terminal domain (CTD) of the HIV-1 capsid. Our discovery effort will be based on our extensive preliminary data obtained with several rationally designed ?-helically stable cell- penetrating peptides and small-molecule lead compounds. Our approach will take advantage of our recent solution structure of one of the cell-penetrating peptides (NYAD-1) in complex with the CTD. We will optimize the lead peptides and small-molecule compounds using a combination of medicinal chemistry and computer-aided design approaches. In addition, we will continue searching the ZINC database by docking- based virtual screening techniques to identify small drug-like compounds which have the potential to bind to the hydrophobic pocket and the dimer interface and inhibit viral assembly and maturation. We will elucidate in detail the molecular mechanism by which these inhibitors disrupt HIV-1 assembly and maturation. The goals of the proposed studies are two-fold: 1) To use structure-based rational design to develop potent cell- penetrating peptides and small molecules that inhibit HIV-1 assembly and maturation and 2) To establish the mechanism by which these inhibitors disrupt HIV-1 assembly and maturation. The capsid CTD-based inhibitors identified in these studies will serve as probes for elucidating the underlying structural requirements in forming immature and mature virus particles. The studies described in this proposal may lead to the development of a new class of antiretroviral therapeutics targeting the HIV-1 capsid. PUBLIC HEALTH RELEVANCE: The proposal will seek to design novel HIV-1 inhibitors, which target the highly conserved areas of capsid protein and inhibit viral assembly and maturation. Since there is no drug yet available against HIV-1 assembly and maturation, this study may lead to the development of new class of HIV-1 drugs. In addition, understanding the detail mechanism of action of these inhibitors may also have broader implication in overall understanding of viral assembly and maturation. These inhibitors may also serve as probes in elucidating the underlying structural requirements in forming immature and mature virus particles, which are critical for viral assembly and infectivity.

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）的引入显着降低了 HIV-1 感染者的发病率和死亡率。然而，耐药性的发展对患者可用的治疗选择构成了严重威胁。此外，最近有关默克 HIV-1 疫苗和几种杀菌剂临床试验失败的报道强调了识别和开发抗 HIV-1 药物新靶点的迫切需要。新药将扩大联合治疗的范围，并有助于减少耐药性 HIV-1 变异体的发展。 HIV-1 Gag 多蛋白的衣壳结构域在病毒组装和成熟中发挥着关键作用，因此代表了开发艾滋病治疗药物的重要潜在靶点。我们建议开发针对高度保守的疏水口袋和 HIV-1 衣壳 C 端结构域 (CTD) 中的二聚化界面的新型抗 HIV-1 药物。我们的发现工作将基于我们通过几种合理设计的β-螺旋稳定细胞穿透肽和小分子先导化合物获得的广泛初步数据。我们的方法将利用我们最近与 CTD 复合的一种细胞穿透肽 (NYAD-1) 的解决方案结构。我们将结合药物化学和计算机辅助设计方法来优化先导肽和小分子化合物。此外，我们将继续通过基于对接的虚拟筛选技术搜索ZINC数据库，以识别具有与疏水口袋和二聚体界面结合并抑制病毒组装和成熟潜力的小药物样化合物。我们将详细阐明这些抑制剂破坏 HIV-1 组装和成熟的分子机制。拟议研究的目标有两个：1) 使用基于结构的合理设计来开发有效的细胞穿透肽和小分子，抑制 HIV-1 组装和成熟；2) 建立这些抑制剂破坏 HIV-1 的机制。 HIV-1 的组装和成熟。这些研究中鉴定出的基于衣壳 CTD 的抑制剂将作为探针来阐明形成未成熟和成熟病毒颗粒的基本结构要求。该提案中描述的研究可能会导致开发一类针对 HIV-1 衣壳的新型抗逆转录病毒疗法。公共健康相关性：该提案将寻求设计新型 HIV-1 抑制剂，该抑制剂针对衣壳蛋白的高度保守区域并抑制病毒组装和成熟。由于目前还没有针对 HIV-1 组装和成熟的药物，这项研究可能会导致新型 HIV-1 药物的开发。此外，了解这些抑制剂的详细作用机制也可能对全面了解病毒组装和成熟具有更广泛的意义。这些抑制剂还可以作为探针，阐明形成未成熟和成熟病毒颗粒的基本结构要求，这对于病毒组装和感染性至关重要。