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

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

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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一种针对人类免疫缺陷病毒1型（HIV-1）感染的新型抑制途径。 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临床方法依赖于多个鸡尾酒，以多种感染的阶段和病毒繁殖的菜单。第二个目的是使用模板约束的环状肽病毒进入抑制剂来阐明与GP120上与磺嘧啶结合位点结合的辅助相互作用。最终目的是开发针对高吞吐量筛选标识的艾滋病毒进入途径的小分子的结构活动关系（SAR）。这些目标将使用分子设计，化学合成，计算建模，高吞吐量筛选和生物学测定的组合来实现。总之，这三个目标阐明了针对HIV-1感染的新抑制途径。艾滋病毒感染的数量不断增加以及病毒融合抑制剂在艾滋病毒临床治疗中的最新成功强调，需要识别和利用其他病毒式抑制剂。虽然已识别出与CD4激活的结合与细胞表面CO受体的结合已识别几年，但直到最近才提出了GP120上磺胺酪氨酸结合位点的明确证据。目前，尚无针对GP120在CO受体结合中的作用的已知抑制剂。这些最近的发现引发了重大问题。我们可以利用GP120上的磺胺酪氨酸结合位点抑制病毒入口吗？磺胺酪氨酸结合位点在介导各种病毒表型中的病毒进入中的作用有多一般？公共卫生相关性：回答这些问题既提供了对HIV-1 Entry机制的基本了解，又提供了损害HIV感染的新工具。