Capsid-mediated interactions in HIV assembly

描述(申请人提供)：由艾滋病毒逆转录病毒引起的艾滋病流行是由传染病病原体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供应有限，以及出现具有抗药性的艾滋病毒毒株，这些都突出表明，仍有必要确定和开发新的艾滋病毒预防和治疗方法、药物靶标和药物。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以及缺乏适合于药物筛选和先导优化的有效组装分析，这一方向的进展缓慢。我们最近的结果揭示了锌指相关扫描域和逆转录病毒衣壳C末端结构域(CA-CTD)之间的进化关系，并提示了逆转录病毒组装中衣壳介导的Gag寡聚的机制。这一建议的主要假设是，在扫描结构中观察到的结构域交换的二聚体代表了病毒组装过程中采用的CA-CTD的关键构象。由扫描结构提供的功能线索将被用于识别衣壳二聚的关键分子决定因素，并研究扫描样结构域交换的CA-CTD二聚体的拟议作用(目标1)。通过高通量筛选和合理设计，将建立灵敏和可靠的CA-CTD二聚分析方法，用于衣壳二聚抑制剂的鉴定。将对已确定化合物的抗艾滋病毒潜力进行评估(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).