Capsid-mediated interactions in HIV assembly

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性病原体对全球健康构成的主要威胁之一。在发展中国家，昂贵的抗艾滋病毒药物供应有限，以及耐药艾滋病毒毒株的出现，突出表明继续需要确定和开发新的艾滋病毒预防和治疗方法、药物靶点和药物。破坏病毒组装是一种很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导联优化的有效组装分析，这一方向的进展一直缓慢。我们最近的研究结果揭示了锌指相关的SCAN结构域和逆转录病毒衣壳c端结构域（CA-CTD）之间的进化关系，并提出了一种衣壳介导的逆转录病毒组装中Gag寡聚化的机制。这一提议的主要假设是，在扫描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，并研究类似SCAN的结构域交换CA-CTD二聚体的拟议作用（目的1）。通过高通量筛选和合理设计，将开发出灵敏、可靠的CA-CTD二聚化检测方法，并用于衣壳二聚化抑制剂的鉴定。将评估鉴定的化合物的抗hiv潜力（目标2）。

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).