Capsid-mediated interactions in HIV assembly

HIV组装中衣壳介导的相互作用

• 批准号: 7230861
• 负责人: DMITRI N IVANOV
• 金额: $ 22.74万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230861
• 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病患者对全球健康构成的主要威胁之一。在发展中国家，昂贵的抗HIV药物的可用性有限，以及耐药艾滋病毒菌株的出现，突显了持续的鉴定和开发新型HIV预防和治疗方法，药物靶标和药物的需求。病毒组装的破坏是一种有希望的抗病毒治疗策略，但是由于病毒组装过程的多价性质，该方向的进展速度很慢，并且由于缺乏适合药物筛查和铅优化的有效组装测定法。我们最近的结果表明，锌指相关的扫描结构域与逆转录病毒C末端C末端结构域（CA-CTD）之间存在进化关系，并提出了一种在逆转录病毒组装中的衣壳介导的GAG寡聚的机制。该提议的主要假设是在扫描结构中观察到的域交换二聚体代表了病毒装配过程中采用的CA-CTD的临界构象。扫描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，并研究类似扫描域的CA-CTD二聚体所提出的作用（AIM 1）。通过高吞吐量筛选和合理设计，将开发并使用对CA-CTD二聚化的敏感和健壮的测定。将评估已确定化合物的抗HIV潜力（AIM 2）。