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确定HIV-1 Env蛋白细胞进入机器作为疾病干预目标的脆弱性，方法是确定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南。抑制艾滋病毒-1最初进入宿主细胞仍然是预防病毒感染和传播的一种令人信服但难以捉摸的手段。HIV-1Env的抑制剂，既可以阻止细胞相互作用， 在受体相遇或破坏受体诱导的环状病毒构象变化之前，灭活三聚体病毒刺突蛋白复合体将有望抑制最初的HIV-1感染。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，这是全球健康的优先事项，也可以治疗已经感染的人。尽管Env抑制剂在艾滋病干预中具有巨大的潜力，但Env蛋白的结构复杂性和多态给研究带来了巨大的挑战。尽管如此，我们计划的努力已经导致了两类Env gp120抑制剂的开发，它们利用了高度保守的CD4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与病毒环境三聚体结合并导致病毒灭活和阻止病毒进入宿主细胞的独特途径。我们的项目处于通过最先进的基于结构和机制的方法利用这些新结果的理想位置，这些方法是由我们的多机构研究团队合作实现的，他们在蛋白质-蛋白质相互作用的高分辨率结构确定、结构动力学、动力学、热力学和结构机制、化学设计和合成、计算方法和病毒学方面拥有丰富的专业知识。我们将把这个团队的方法应用于我们已经开发的抑制剂化学类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中发现的新的抑制剂化学类型。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-1Env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.