Structure-Based Antagonism of HIV-1 Envelope Function in Cell Entry

描述（由申请人提供）：该计划的总体目标是通过鉴定Env抑制剂，定义其结构作用机制，并使用结构-机制框架作为优化拮抗剂功能的指导，确定HIV-1 Env蛋白细胞进入机器作为疾病干预靶点的脆弱性。抑制HIV-1最初进入宿主细胞仍然是预防病毒感染和传播的一种引人注目但难以捉摸的手段。HIV-1 Env的抑制剂可以阻断细胞相互作用， 在受体遭遇前阻断三聚体病毒刺突蛋白复合物或破坏Env中受体诱导的构象变化将具有抑制初始HIV-1感染的巨大希望。这种抑制剂将提供针对病毒的分子武器，既可以防止艾滋病传播，也可以治疗已经感染的个体。尽管Env抑制剂用于AIDS干预的巨大潜力，但Env蛋白的结构复杂性和多态性对进展提出了重大挑战。尽管如此，我们计划的努力已经导致开发了两类Env gp 120抑制剂，它们利用高度保守的CD 4结合位点，但具有非常不同的作用模式。对这些抑制剂的研究已经确定了独特的途径来接合病毒Env三聚体并导致病毒灭活和阻断病毒进入宿主细胞。我们的计划非常适合通过最先进的结构和机制为基础的方法利用这些新成果，通过我们的多机构研究团队的协作性质实现，在高分辨率结构测定，结构动力学，动力学，热力学和蛋白质相互作用的结构机制，化学设计和合成，计算方法和病毒学方面具有强大的专业知识。我们将把这种团队方法应用于我们已经开发的抑制剂化学型的基于结构的设计和机理研究，以及在我们自己和其他实验室发现的新抑制剂化学型。总体而言，该计划将提供一个基础广泛的研究基础设施，以确定发现阻断HIV-1 Env功能的预防和治疗药物的新途径。

DESCRIPTION (provided by applicant): The overarching goal of this Program is to determine the vulnerabilities of the HIV-1 Env protein cell entry machine as a target for disease intervention by identifying Env inhibitors, defining their structural mechanisms of action, and using a structure-mechanism framework as a guide to optimize antagonist functions. Inhibition of the initial entry of HIV-1 into host cells remains a compelling, yet elusive means to prevent infection and spread of the virus. Inhibitors of HIV-1 Env that can either block cell interactions, inactivate the trimeric virus spike protein complex before receptor encounter or disrupt receptor-induced conformational changes in the Env would hold great promise of inhibiting initial HIV-1 infection. Such inhibitors would provide virus-targeted molecular weapons both to prevent AIDS transmission, a global health priority, and to treat already-infected individuals. In spite of the great potential of Env inhibitors for AIDS intervention, structural complexity and polymorphisms of the Env proteins have presented significant challenges to progress. Nonetheless, the efforts of our Program have led to the development of two classes of Env gp120 inhibitors that utilize the highly conserved CD4 binding site, but with very different modes of action. Investigation of these inhibitors has defined unique pathways to engage the virus Env trimer and cause both inactivation of the virus and blockade of virus entry into the host cell. Our Program is ideally positioned to take advantage of these new results through state-of-the-art structure- and mechanism-based approaches, achieved by the collaborative nature of our multi-institutional research team, with strong expertise in high-resolution structure determination, structural dynamics, kinetic, thermodynamic and structural mechanisms of protein-protein interactions, chemical design and synthesis, computational methods, and virology. We will apply this team approach to structure-based design and mechanistic investigations of inhibitor chemotypes that we have already developed, and new inhibitor chemotypes as they are discovered in our own and other laboratories. Overall, the Program will provide a broad-based research infrastructure to identify new paths for the discovery of preventive and therapeutic agents that block HIV-1 Env function.