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

gp 120 上 CCR5 识别位点的 HIV-I 抑制拮抗剂工具

基本信息

批准号：
7546771
负责人：
Jonathan G Rudick
金额：
$ 4.96万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546771
关键词：
Address Binding Binding Sites Biological Assay CCR5 gene Cell surface Chemokine (C-C Motif) Receptor 5 Clinical Clinical Treatment Complex Computer Simulation Computing Methodologies Cyclic Peptides Development Dose Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Immune Infection Inhibitory Concentration 50 Libraries Mediating Methodology Molecular Molecular Conformation N-terminal Numbers Pathway interactions Peptides Pharmaceutical Preparations Phase Phenotype Public Health Reproduction Research Role Site Solid Staging Stress Structure-Activity Relationship Testing Therapeutic Tropism United States National Institutes of Health Viral Virus Virus Diseases Virus Inhibitors base chemical synthesis chemokine receptor chemotherapy design gp-120 Antigen high throughput screening inhibitor/antagonist molecular modeling neutralizing antibody novel prevent receptor receptor binding repository response small molecule small molecule libraries success tool tyrosine O-sulfate

项目摘要

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.

描述（由申请人提供）：本文提出的研究旨在阐明针对人类免疫缺陷病毒1型（HIV-1）感染的新抑制途径。我们假设，包膜糖蛋白 120 (gp120) 的磺基酪氨酸结合位点可用于阻止与 (3 趋化因子受体 CCR5，以及潜在的其他趋化因子受体) 的结合，这是病毒进入所必需的。迄今为止，尚无已知的抑制剂鉴于 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的多个阶段的多药物混合物。为实现这一目标，我们设定了三个具体目标，第一个目标是利用 CCR5 N 末端阐明两个必需的磺基酪氨酸残基（Tys10 和 Tys14）的作用。构象限制的螺旋 N 末端磺肽的第二个目的是阐明使用 gp120 与磺基酪氨酸结合位点结合所涉及的辅助相互作用。模板限制环肽病毒进入抑制剂。最终目标是开发针对通过高通量筛选确定的 HIV 进入途径的小分子的结构活性关系 (SAR)。这些目标将通过结合分子设计、化学合成、计算建模、高通量筛选和生物测定来实现。这三个目标共同阐明了一种针对 HIV-1 感染的新抑制途径。 HIV 感染数量的不断增加以及病毒融合抑制剂最近在 HIV 临床治疗中取得的成功强调需要识别和开发其他病毒进入抑制剂。虽然参与 CD4 激活 gp120 与细胞表面辅受体结合的结构成分已被认识多年，但 gp120 上磺基酪氨酸结合位点的明确证据直到最近才被提出。目前还没有已知的抑制剂针对 gp120 在辅受体结合中的作用。这些最近的发现提出了重大问题。我们可以利用 gp120 上的磺基酪氨酸结合位点来抑制病毒进入吗？磺基酪氨酸结合位点在介导病毒进入各种病毒表型中的作用有多普遍？公共卫生相关性：回答这些问题既可以让我们对 HIV-1 进入机制有一个基本的了解，也可以发现削弱 HIV 感染的新工具。