Capsid-mediated interactions in HIV assembly

HIV组装中衣壳介导的相互作用

• 批准号: 7364649
• 负责人: DMITRI N IVANOV
• 金额: $ 24.74万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364649
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Adopted; Amino Acid Sequence; Amino Acids; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Architecture; Biological Assay; C-terminal; Capsid; Capsid Proteins; Characteristics; Complex; Data; Defect; Development; Dimerization; Disruption; Dominant-Negative Mutation; Drug Delivery Systems; Due Process; Elements; Epidemic; Event; Gagging; HIV; HIV Budding; HIV drug resistance; Health; Homologous Gene; Human; In Vitro; Infectious Agent; Lead; Libraries; Life Cycle Stages; Long Terminal Repeats; Maps; Mass Spectrum Analysis; Mediating; Methods; Modeling; Molecular; Molecular Conformation; Mutagenesis; NMR Spectroscopy; Nature; Peptides; Pharmaceutical Preparations; Phenotype; Preclinical Drug Evaluation; Process; Property; Proteins; Research Personnel; Resistance; Retrotransposon; Retroviridae; Role; Scanning; Side; Solutions; Stretching; Structure; Testing; Viral; Viral Proteins; Virus-like particle; Zinc Fingers; base; crosslink; design; dimer; gag Gene Products; high throughput screening; in vivo; inhibitor/antagonist; insight; mutant; novel; particle; pathogen; programs; small molecule

DESCRIPTION (provided by applicant): The AIDS epidemic caused by the HIV retrovirus is one of the leading threats posed to global health by an infectious agent. Limited availability of expensive anti-HIV drugs in the developing world, as well as emergence of drug-resistant HIV strains, highlight the continued need for identification and development of novel HIV prevention and treatment methods, drug targets and drugs. Disruption of viral assembly is a promising antiviral treatment strategy, but the progress in this direction has been slow due to the multivalent nature of the viral assembly process and due to the lack of efficient assembly assays suitable for drug screening and lead optimization. Our recent results revealed an evolutionary relationship between the zinc- finger associated SCAN domain and the retroviral capsid C-terminal domain (CA-CTD), and suggested a mechanism for capsid-mediated Gag oligomerization in retroviral assembly. The main hypothesis of this proposal is that the domain-swapped dimer observed in the SCAN structure represents a critical conformation of CA-CTD adopted during viral assembly. The functional clues provided by the SCAN structure will be used to identify critical molecular determinants of capsid dimerization, and to investigate the proposed role of the SCAN-like domain-swapped CA-CTD dimer (Aim 1). Sensitive and robust assays of CA-CTD dimerization will be developed and used for identification of capsid dimerization inhibitors by high throughput screening and rational design. The anti-HIV potential of the identified compounds will be evaluated (Aim 2).

描述（由申请人提供）：由 HIV 逆转录病毒引起的艾滋病流行是传染原对全球健康构成的主要威胁之一。发展中国家昂贵的抗艾滋病毒药物的供应有限，以及耐药性艾滋病毒株的出现，凸显了对新型艾滋病毒预防和治疗方法、药物靶点和药物的持续需求。破坏病毒组装是一种有前途的抗病毒治疗策略，但由于病毒组装过程的多价性质以及缺乏适合药物筛选和先导化合物优化的有效组装测定，该方向的进展缓慢。我们最近的结果揭示了锌指相关的SCAN结构域和逆转录病毒衣壳C末端结构域（CA-CTD）之间的进化关系，并提出了逆转录病毒组装中衣壳介导的Gag寡聚化的机制。该提议的主要假设是，在 SCAN 结构中观察到的结构域交换二聚体代表了病毒组装过程中采用的 CA-CTD 的关键构象。 SCAN 结构提供的功能线索将用于识别衣壳二聚化的关键分子决定因素，并研究 SCAN 样结构域交换 CA-CTD 二聚体的拟议作用（目标 1）。将开发灵敏且稳健的 CA-CTD 二聚化检测方法，并用于通过高通量筛选和合理设计来鉴定衣壳二聚化抑制剂。将评估已鉴定化合物的抗 HIV 潜力（目标 2）。