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

• 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
• 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

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新的抗人类免疫缺陷病毒1型（HIV-1）感染的抑制途径。我们假设包膜糖蛋白120（gp 120）的磺基酪氨酸结合位点可被利用来阻止与β趋化因子受体CCR 5和潜在的其它趋化因子受体的结合，这是病毒进入所必需的。到目前为止，还没有已知的针对该受体的抑制剂。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多个阶段的多药物鸡尾酒。增加可用靶点的菜单解决了艾滋病毒化疗的一个关键挑战。为了实现这一目标，我们设定了三个具体目标。第一个是澄清的作用，两个必不可少的磺基酪氨酸残基（Tys 10和Tys 14）在CCR 5的N端使用构象约束的螺旋N端磺肽。第二个目的是阐明辅助相互作用参与结合的磺基酪氨酸结合位点的gp 120使用模板限制环肽病毒进入抑制剂。最终的目标是开发针对通过高通量筛选鉴定的HIV进入途径的小分子的结构活性关系（SAR）。这些目标将使用分子设计，化学合成，计算建模，高通量筛选和生物测定的组合来实现。这三个目标一起阐明了一个新的抑制HIV-1感染的途径。HIV感染数量的持续上升和最近病毒融合抑制剂在HIV临床治疗中的成功强调了鉴定和开发其他病毒进入抑制剂的需要。虽然参与CD 4激活的gp 120与细胞表面co受体结合的结构成分已经被认识了几年，但gp 120上磺基酪氨酸结合位点的明确证据最近才被提出。目前还没有已知的抑制剂靶向gp 120在co受体结合中的作用。最近的这些发现提出了一些重大问题。我们能否利用gp 120上的磺基酪氨酸结合位点来抑制病毒进入？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：对这些问题的探讨，既提供了对HIV-1进入机制的基本理解，也揭示了削弱HIV感染的新工具。