Tools for HIV-I Inhibition Antagonists for the CCR5 Recognition Site on gp 120

描述（由申请人提供）：本文提出的研究旨在阐明一种新的抑制人类免疫缺陷病毒1型（HIV-1）感染的途径。我们假设包膜糖蛋白120 （gp120）的巯基酪氨酸结合位点可以被利用来阻止与趋化因子受体CCR5和其他趋化因子受体的结合，这是病毒进入所必需的。到目前为止，还没有已知的针对这种受体的抑制剂。鉴于hiv -1对免疫和治疗挑战的高度适应性反应，最有效的临床方法依赖于针对感染和病毒繁殖的多个阶段的多种药物鸡尾酒疗法。增加可用靶点的菜单解决了艾滋病毒化疗中的一个关键挑战。为了实现这一目标，我们设定了三个具体目标。首先是利用构象约束的螺旋N端巯基肽阐明CCR5 N端两个必需的硫代酪氨酸残基（TyslO和Tys14）的作用。第二个目的是阐明使用模板约束的环肽病毒进入抑制剂与gp120上的硫代酪氨酸结合位点结合所涉及的辅助相互作用。最终目的是建立高通量筛选确定的靶向HIV进入途径的小分子结构活性关系（SARs）。这些目标将通过结合分子设计、化学合成、计算建模、高通量筛选和生物分析来实现。综上所述，这三个目标阐明了一种新的抑制HIV-1感染的途径。艾滋病毒感染人数的不断增加和最近病毒融合抑制剂在艾滋病毒临床治疗中的成功强调需要识别和开发额外的病毒进入抑制剂。虽然参与cd4激活的gp120与细胞表面共受体结合的结构成分已经被识别了好几年，但gp120上的巯基酪氨酸结合位点的明确证据直到最近才被提出。目前还没有已知的靶向gp120在共受体结合中的作用的抑制剂。这些最近的发现提出了重要的问题。我们能否利用gp120上的硫代酪氨酸结合位点来抑制病毒进入？在各种病毒表型中，巯基酪氨酸结合位点在介导病毒进入中的作用有多普遍？

DESCRIPTION (provided by applicant): The research proposed herein aims to elucidate a novel inhibitory pathway against human immunodeficiency virus type 1 (HIV-1) infection. We hypothesize that a sulfotyrosine binding site of the envelope glycoprotein 120 (gp120) can be exploited to prevent binding to the (3 chemokine receptor CCR5, and potentially other chemokine receptors, which is requisite for viral entry. As yet there are no inhibitors known to target this receptor. Given the highly adaptive response of HIV-1to immune and therapeutic challenges, the most effective clinical approaches rely upon multi-drug cocktails targeting multiple stages of infection and viral reproduction. Adding to the menu of available targets addresses a key challenge in HIV chemotherapy. Toward this goal we set three specific aims. The first is to clarify the roles of the two essential sulfotyrosine residues (TyslO and Tys14) in the CCR5 N terminus using conformationally constrained helical N terminal sulfopeptides. The second aim is to elucidate the auxiliary interactions involved in binding to the sulfotyrosine binding site on gp120 using template constrained cyclic peptide viral entry inhibitors. The final aim is to develop structure activity relationships (SARs) for small molecule targeting the HIV entry pathway identified by high throughput screening. These goals will be approached using a combination of molecular design, chemical synthesis, computational modeling, high throughput screening, and biological assays. Taken together these three aims elucidate a new inhibitory pathway against HIV-1 infection. Continually rising numbers of HIV infections and the recent success of viral fusion inhibitors in the clinical treatment of HIV stress the need to identify and exploit additional viral entry inhibitors. While structural components involved in the CD4-activated binding of gp120 to cell surface co receptors have been recognized for several years, clear evidence of a sulfotyrosine binding site on gp120 has only recently been presented. At present there are no known inhibitors targeting gp120's role in co receptor binding. These recent findings raise significant questions. Can we exploit the sulfotyrosine binding site on gp120 to suppress viral entry? How general is the role of the sulfotyrosine binding site in mediating viral entry among various viral phenotypes? PUBLIC HEALTH RELEVANCE: Answering these questions provides both a fundamental understanding of the mechanism of HIV-1entry and uncovers new tools with which to impair HIV infections.