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: 8433532
• 负责人: Asim K Debnath
• 金额: $ 49.45万
• 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: 2009-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433532
• 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 Targeting; Drug resistance; Failure; Goals; HIV-1; 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; Quantitative Structure-Activity Relationship; Reporting; Resolution; Role; Site; Solutions; Structure; Techniques; Testing; Vaccines; Variant; Viral; Virion; Virus; Virus Assembly; Virus-like particle; abstracting; base; chemotherapy; cytotoxicity; design; dimer; gag Gene Products; indexing; inhibitor/antagonist; microbicide; monomer; mortality; novel; prevent; process optimization; programs; research study; screening; small molecule; therapeutic target; virtual

Abstract 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.

摘要 高效抗逆转录病毒疗法（HAART）的引入， 降低了HIV-1感染者的发病率和死亡率。但 耐药性的发展对现有的治疗方案构成严重威胁 给病人。此外，最近关于默克公司HIV-1临床试验失败的报告 疫苗和几种杀微生物剂加强了识别和开发新的 抗HIV-1药物的靶点。新型药物将拓宽联合治疗的范围 并将有助于减少耐药HIV-1变异的发展。衣壳 HIV-1 Gag多蛋白的结构域在病毒组装中起关键作用， 成熟，因此代表了开发药物的重要潜在目标 用于艾滋病治疗。我们建议开发新的抗HIV-1药物，靶向高度 保守的疏水口袋和C-末端结构域中的二聚化界面 (CTD)HIV-1外壳的。我们的探索工作将基于我们广泛的 用几个合理设计的螺旋稳定电池获得的初步数据， 穿透肽和小分子先导化合物。我们的方法将采取 我们最近的一种细胞穿透肽（NYAD- 1)和CTD有关系我们将优化先导肽和小分子 药物化学和计算机辅助设计相结合 接近。此外，我们将通过对接继续搜索ZINC数据库- 基于虚拟筛选技术，以确定具有 结合疏水口袋和二聚体界面并抑制病毒的潜力 组装和成熟。我们将详细阐明 这些抑制剂破坏HIV-1的装配和成熟。拟议的目标 研究是两方面的：1）使用基于结构的合理设计来开发有效的细胞- 抑制HIV-1装配和成熟的穿透肽和小分子 以及2）建立这些抑制剂破坏HIV-1组装的机制 和成熟。在这些研究中鉴定的基于衣壳CTD的抑制剂将用于 作为阐明形成未成熟和未成熟的生物体的潜在结构要求的探针， 成熟病毒颗粒本提案中所述的研究可能会导致 开发了一类新的靶向HIV-1衣壳的抗逆转录病毒疗法。

项目成果

Synthesis of 2-Oxo-1, 2-Dihydroquinoline Chemotype with Multiple Attachment Points as Novel Screening Compounds for Drug Discovery.

具有多个附着点的 2-Oxo-1, 2-二氢喹啉化学型的合成作为药物发现的新型筛选化合物。

• 发表时间: 2016
• 期刊: JSM Chemistry
• 作者: Kurkin,AlexanderV;Altieri,Andrea;Andreev,IvanA;Debnath,AsimK
• 通讯作者: Debnath,AsimK

Design of antiviral stapled peptides containing a biphenyl cross-linker.

• DOI: 10.1016/j.bmcl.2014.02.038
• 发表时间: 2014-04-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Muppidi, Avinash;Zhang, Hongtao;Curreli, Francesca;Li, Nan;Debnath, Asim K.;Lin, Qing
• 通讯作者: Lin, Qing

Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid.

• DOI: 10.1016/j.bmc.2010.11.045
• 发表时间: 2011-01-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Curreli, Francesca;Zhang, Hongtao;Zhang, Xihui;Pyatkin, Ilya;Victor, Zagorodnikov;Altieri, Andrea;Debnath, Asim K.
• 通讯作者: Debnath, Asim K.