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

总体方案项目摘要 该计划项目的目标是发现、设计、合成、优化和验证小分子 HIV-1包膜(Env)三聚体的拮抗剂及其分子、病毒学和 确定攻击艾滋病毒的潜在预防和治疗方法的细胞作用机制- 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，因此是预防和干预病毒的关键第一目标 感染。能够以足够的亲和力、特异性和广度结合到序列保守和 Env上的功能中心应该能够抑制、灭活和/或过早激活病毒上的Env，并且 在受感染细胞上。通过这样做，这种化合物可以阻止细胞感染和新的感染性疾病的形成。 病毒，并为根除感染细胞做好准备。我们的计划项目取得了重大进展 在过去的5年中，识别变构或竞争性阻断[1]的小分子HIV-1 Env抑制剂 HIV-1细胞受体相互作用和细胞感染；[2]不可逆转地使病毒和感染病毒的细胞失活； 以及[3]使细胞对抗体介导的免疫反应敏感。这一进展带来了重要的机遇 鉴定和探讨Env拮抗作用的基本机制。我们的进展将在 通过加深对构象的了解，将极大地促进小分子抑制剂的开发 HIV-1环境三聚体的状态、动态和高分辨率结构，以及对这一点的理解 分子机器被激活，以调节病毒和细胞膜之间的融合。反过来， 我们开发的小分子抑制剂将有助于理解环境三聚体的结构和动力学 程序项目，起化学探针的作用，以抑制、捕获或激活特定的构象状态。 小分子的发现、设计、合成、优化和验证将加强识别 关于艾滋病毒-1/艾滋病的预防、治疗和根除干预措施。我们将推行全面的 研究HIV-1环境病毒拮抗作用的机械论方法。为了做到这一点，7名调查人员组织了5次 项目和3个核心将采取多学科、综合和协同的办法。我知道没有单曲 集团可以单独取得成功，该计划建立了高度协作和高效的基础设施，具有 早期讨论想法、快速交流新发现和最有效策略的氛围 为实现研究目标进行了验证。该计划项目将建立在经验丰富的 调查人员以及两名新的调查人员应对新的事态发展和挑战。

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.