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

我们在这个项目中的总体目标是了解 人免疫缺陷病毒（HIV-1）gp 120包膜糖蛋白的配体抑制 病毒入侵HIV-1感染是由病毒进入宿主细胞开始的。进入过程取决于 在病毒与宿主的初始附着上，并且该附着过程的分子组成是 知道的HIV-1细胞识别通过病毒刺突上的包膜蛋白发生， gp 120/gp 41复合体。gp 120和细胞受体之间的相互作用似乎在细胞凋亡中起着核心作用。 在病毒进入中。因此，设计gp 120与细胞受体相互作用的拮抗剂是本发明的核心。 计划项目的目标。我们将利用一个全面的，跨学科的，多组 将联合收割机化学合成、高分辨率结构测定、热力学 以及动力学结合分析、细胞感染分析、重组蛋白生产和诱变分析。 分析和计算建模。我们已经证明了我们利用这一点的能力 作为一个团队的全面方法，并相信我们的经验，到目前为止，沿着与目前的开始 在我们的研究中达到的要点将成功地导致机械的重要进展 理解和生产方法的HIV-1进入抑制剂。该项目将有5个 具体的目标。(1)识别与功能重要区域相互作用的新型化合物 HIV-1 gp 120糖蛋白。(2)确定化合物在gp 120上的结合位点 糖蛋白(3)阐明化合物抑制HIV-1进入的机制。 (4)优化gp 120结合化合物的抗病毒效力。(5)了解变化的影响 HIV-1包膜糖蛋白对化合物抗病毒功效的影响。我们将实现这些目标 通过五个项目和两个核心来实现目标。项目1：HIV-1进入抑制的结构分析 （Hendrickson）;项目2：HIV-1进入的肽激发的竞争性和变构抑制剂（Chaiken）; 项目3：小分子CD 4-gp 120拮抗剂的发现和合成（Smith）;项目4： 组装和抑制热力学（Freire）;项目5：基于结构的HIV-1拮抗作用 细胞进入中的包膜功能（Sodroski）;核心A：计算建模（LaLonde）;核心B：蛋白质 技术（Chaiken）。该项目将研究小分子抑制 HIV-1病毒进入，并将确定候选抑制剂作为潜在的拮抗剂，用于艾滋病预防， 治疗由于许多参与疾病发病机制的病毒蛋白质表现出可塑性， 对于HIV-1 gp 120的发现，我们相信我们为gp 120系统开发的方法将提供 预防和治疗其他疾病的实验范例

Our overall goal in this program project is to understand the potential of ligands of the human immunodeficiency virus (HIV-1) gp120 envelope glycoprotein to inhibit virus entry. HIV-1 infection is initiated by entry of the virus into host cells. The entry process depends on initial attachment of virus with host, and the molecular components of this attachment process are known. HIV-1 cell recognition occurs through envelope proteins on the viral spike, a heterotrimer of the gp120/gp41 complex. The interactions between gp120 and cell receptors appear to play the central role in viral entry. Hence, the design of antagonists of gp120 interactions with cell receptors is the central objective of the Program Project. We will utilize a comprehensive, interdisciplinary, multi-group approach that will combine chemical synthesis, high-resolution structure determination, thermodynamic and kinetic binding analyses, cell infection analyses, recombinant protein production and mutagenic analyses and computational modeling. We have already demonstrated our capacity to utilize this comprehensive approach as a team, and believe our experiences so far along with current starting points arrived at in our studies will successfully lead to important advances in mechanistic understanding and productive approaches to HIV-1 entry inhibitors. The Program Project will have 5 overarching specific aims. (1) Identify novel compounds that interact with functionally important regions of the HIV-1 gp120 glycoprotein. (2) Define the binding sites of the compounds on the gp120 glycoprotein. (3) Elucidate the mechanism of inhibition of HIV-1 entry associated with the compounds. (4) Optimize gp120-binding compounds for antiviral potency. (5) Understand the impact of variation in the HIV-1 envelope glycoproteins on the antiviral efficacy of the compounds. We will accomplish these aims through 5 Projects and 2 Cores. Project 1: Structure analysis of HIV-1 entry inhibition (Hendrickson); Project 2: Peptide-inspired competitive and allosteric inhibitors of HIV-1 entry (Chaiken); Project 3: Discovery and synthesis of small molecule CD4-gp120 antagonists (Smith); Project 4: Assembly and inhibition thermodynamics (Freire); Project 5: Structure-based antagonism of HIV-1 envelope function in cell entry (Sodroski); Core A: Computational modeling (LaLonde); Core B: Protein technologies (Chaiken). This program project will examine the potential of small molecules to inhibit HIV-1 viral entry and will identify candidate inhibitors as potential antagonists for AIDS prevention and treatment. Since many viral proteins involved in disease pathogenesis exhibit the type of plasticity found for HIV-1 gp120, we believe that the approaches we develop for the gp120 system will provide experimental paradigms for prevention and treatment of other diseases as well