CCR5 & CXCR4 Antagonist & Agonist Binding Site Structure

CCR5

• 批准号: 7008813
• 负责人: EDWARD A DRATZ
• 金额: $ 34.54万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008813
• 关键词: HIV infections; antiAIDS agent; antiviral agents; binding sites; chemokine receptor; drug design /synthesis /production; drug resistance; laboratory mouse; protein structure function; receptor sensitivity; virus infection mechanism; virus receptors

DESCRIPTION (provided by applicant): Problems of drug resistance, latent viral reservoirs, and the toxic effects of current anti-HIV drugs call for the development of new anti-retrovirals with different modes of action. A promising approach for drug development is interference with the entry of HIV into cells. HIV entry is a complex process that requires binding of the HIV envelope protein gp120 to a cellular co-receptor (CCR5 or CXCR4). This proposal seeks to enhance understanding of the structure of CCR5 and CXCR4, including the amino acid residues that contribute to alternative modes of antagonist binding and contact residues involved in agonist activation. Virus isolates that require CCR5 for entry are the predominant infectious forms of HIV transmitted from one person to another. Virus strains that require CXCR4 for entry often emerge in the late stages of infection, are considered to be more pathogentic, and correlate with severe loss of CD4+ T lymphocytes and the development of opportunistic infections due to severe immunodeficiency. Several small-molecule antagonists for CCR5 or CXCR4 that block virus infection have been identified as promising drug leads by pharmaceutical companies, but their binding sites on the receptors and the mechanism of HIV blocking are poorly understood. This project will use high-affinity photoactive analogs of antagonist and agonist molecules to examine the interaction sites in CCR5 and CXCR4-and will investigate the roles of the residues at the crosslinking sites by site-specific mutagenesis. We will also investigate the changes in the conformation of CCR5 that result in activation or antagonism of HIV binding, by studying the interaction sites of monoclonal antibodies specific for the antagonist- or agonist-bound conformations of CCR5. The proposed studies will lead to a better understanding of the structure and function of CCR5 and CXCR4 and aim to provide information useful for the design of more potent drugs that inhibit HIV entry while minimizing side effects due to activating or blocking normal functions of CCR5 and CXCR4.

描述（由申请人提供）： 目前抗HIV药物的耐药性、潜伏病毒库和毒性作用等问题要求开发具有不同作用模式的新的抗逆转录病毒药物。药物开发的一种有前途的方法是干扰HIV进入细胞。HIV进入是一个复杂的过程，需要HIV包膜蛋白gp 120与细胞辅助受体（CCR 5或CXCR 4）结合。该提案旨在增强对CCR 5和CXCR 4结构的理解，包括有助于拮抗剂结合的替代模式的氨基酸残基和参与激动剂活化的接触残基。需要CCR 5才能进入的病毒分离株是HIV从一个人传播到另一个人的主要传染形式。需要CXCR 4进入的病毒株通常出现在感染的晚期，被认为更具致病性，并且与CD 4 + T淋巴细胞的严重损失和由于严重免疫缺陷引起的机会性感染的发展相关。几种阻断病毒感染的CCR 5或CXCR 4的小分子拮抗剂已被制药公司确定为有前途的药物先导，但对它们在受体上的结合位点和HIV阻断机制知之甚少。本项目将使用拮抗剂和激动剂分子的高亲和力光活性类似物来检查CCR 5和CXCR 4-中的相互作用位点，并将通过位点特异性诱变来研究交联位点处残基的作用。我们还将调查的CCR 5的构象，导致在激活或拮抗HIV结合的变化，通过研究特异性的拮抗剂或激动剂结合的构象的CCR 5的单克隆抗体的相互作用位点。拟议的研究将有助于更好地了解CCR 5和CXCR 4的结构和功能，并旨在为设计更有效的药物提供有用的信息，这些药物可抑制HIV进入，同时最大限度地减少因激活或阻断CCR 5和CXCR 4的正常功能而产生的副作用。