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

项目总体概要 本项目的目标是小分子的发现、设计、合成、优化和验证 HIV-1包膜（Env）三聚体的拮抗剂，结合其分子、病毒学和 细胞作用机制，以确定潜在的预防和治疗方法，以攻击艾滋病毒- 1艾滋病大流行。HIV-1 Env三聚体是HIV-1暴露表面上唯一的病毒特异性蛋白， 病毒粒子和HIV-1感染细胞上，因此是预防和干预病毒感染的关键第一靶点。 感染可以以足够的亲和力、特异性和广度结合序列保守和 Env上的功能中心应该能够抑制、抑制和/或过早激活病毒上的Env， 感染的细胞。这样做，这些化合物可以阻止细胞感染和新的感染性细胞的形成。 病毒，并为根除感染的细胞做准备。我们的计划项目取得了重大进展 在过去的5年中，确定小分子HIV-1 Env抑制剂，[1]变构或竞争性阻断 HIV-1细胞受体相互作用和细胞感染; [2]不可逆地使病毒和病毒感染的细胞死亡; 和[3]使细胞对抗体介导的免疫应答敏感。这一进展带来了重要的机遇 鉴定和探索Env拮抗作用的基本机制。我们的进展在 通过对构象的深入了解，将大大促进小分子抑制剂的开发。 HIV-1 Env三聚体的状态、动力学和高分辨率结构，以及对这一过程的理解。 分子机器被激活以介导病毒和细胞膜之间的融合。符合要求的细粉则随 了解Env三聚体的结构和动力学将有助于小分子抑制剂，由我们的开发， 程序项目，作为化学探针抑制，捕获或激活特定的构象状态。 小分子的发现、设计、合成、优化和验证将增强鉴定 艾滋病毒1/艾滋病的预防、治疗和根除干预措施。我们将采取全面的 研究HIV-1 Env拮抗作用的机制方法。为了完成这项工作，7名调查人员在5个 项目和3个核心将采取多学科综合和协同的办法。知道没有一个 该计划建立了一个高度协作和高效的基础设施， 在这种氛围中，想法可以尽早讨论，新发现可以迅速交流，最有效的策略也可以 为了实现研究目标。该计划项目将建立在一个经验丰富的小组， 调查员以及两名新的调查员将对新的事态发展和挑战作出反应。

OVERALL PROGRAM PROJECT SUMMARY The goal of this Program Project is the discovery, design, synthesis, optimization and validation of small molecule antagonists of the HIV-1 envelope (Env) trimer, combined with the definition of their molecular, virological and cellular mechanisms of action to identify potential preventive and therapeutic approaches to attack the HIV- 1/AIDS pandemic. The HIV-1 Env trimer is the only virus-specific protein on both the exposed surface of HIV-1 virions and on HIV-1 infected cells, and as such is a crucial first target for prevention and intervention of virus infection. Compounds that can bind with sufficient affinity, specificity and breadth to sequence-conserved and functional centers on Env should be able to inhibit, inactivate, and/or prematurely activate Env on the virus and on infected cells. In so doing, such compounds could block both cell infection and the formation of new infectious viruses, and prime infected cells for eradication. Major advancements have been made in our Program Project during the past 5 years to identify small molecule HIV-1 Env inhibitors that [1] allosterically or competitively block HIV-1 cell receptor interactions and cell infection; [2] irreversibly inactivate both the virus and virus-infected cells; and [3] sensitize cells to antibody-mediated immune responses. This progress opens up important opportunities to identify and explore the fundamental mechanisms of Env antagonism. Our progress going forward in developing small molecule inhibitors will be greatly facilitated by a deepening understanding of conformational states, dynamics and high-resolution structures of the HIV-1 Env trimer, as well as an understanding of how this molecular machine is activated to mediate fusion between viral and cellular membranes. In turn, the understanding of Env trimer structure and dynamics will be aided by small molecule inhibitors, developed by our Program Project, that function as chemical probes to inhibit, entrap or activate specific conformational states. The discovery, design, synthesis, optimization and validation of small molecules will enhance the identification of preventive, therapeutic and eradication interventions for HIV-1/AIDS. We will pursue a comprehensive mechanistic approach to investigate HIV-1 Env antagonism. To accomplish this, 7 investigators organized in 5 projects and 3 cores will pursue a multi-disciplinary integrated and synergistic approach. Knowing that no single group can succeed alone, the program has established a highly collaborative and efficient infrastructure, with an atmosphere where ideas are discussed early, new findings exchanged quickly, and the most effective strategies validated in order to fulfill the research goals. This Program Project will build both on an experienced group of investigators as well as the two new investigators to respond to new developments and challenges.