HIV Fusion Inhibitors

HIV融合抑制剂

• 批准号: 6844579
• 负责人: JAMES P TAM
• 金额: $ 37.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844579
• 关键词: HIV envelope protein gp41; antiAIDS agent; biomimetics; chemical stability; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; guinea pigs; human immunodeficiency virus 1; immunologic substance development /preparation; membrane fusion; pharmacokinetics; protein engineering; protein protein interaction; protein structure function; virus infection mechanism

DESCRIPTION (provided by applicant): This application focuses on the development of a protein mimetic concept for designing HIV-1 entry inhibitors. Protein mimetics are protein-like compounds with covalent-linked oligomers designed to mimic the bioactive quaternary structures of the gp41 trimeric coiled prehairpin and to inhibit its transition to a hairpin of six-helix-bundle commonly involved in the final step of viral membrane fusion. To stabilize their truncated oligomeric helical structure, monomeric strands are constrained by a covalent interstrand linkage at either their amino or carboxyl terminus intended to confer structural stability and to better mimic the bioactive conformation of the fuseogenic state of gp41 than their monomeric peptides. An efficient and chemoselective ligation strategy has been exploited for their preparation using unprotected peptides as monomers to arrive at chemically unambiguous protein mimetics. Preliminary results strongly support the validity of our approach. Protein mimetics exhibit significant improvements in helical structures and resistance to proteolytic degradation. More importantly, several inhibit HIV-1 at sub-nanomolar concentrations that are an order of magnitude more potent than T20, a peptide and the first approved HIV-1 entry inhibitor drug. Our short-term goals are to continue the protein-mimetic concept with added design elements to increase potency, aqueous solubility and proteolytic resistance, and to determine their mechanisms of action by biochemical and biophysical methods. Because the trimeric coiled-coil quaternary structures are found in protein-protein interactions of signaling mechanisms and type-1 envelope protein-mediated viral entry, our long-term goal is to provide a structure-driven approach to design protein mimetic inhibitors relevant to human diseases.

描述(由申请人提供)：本申请专注于开发一种用于设计HIV-1进入抑制剂的蛋白质模拟概念。蛋白质模拟物是一类具有共价连接的寡聚体的蛋白质类化合物，旨在模拟gp41三聚体卷曲的前发夹的生物活性四元结构，并抑制其向六螺旋发夹的转变，通常参与病毒膜融合的最后一步。为了稳定其截断的寡聚螺旋结构，单体链受到其氨基或羧基末端的共价链间连接的约束，目的是提供结构稳定性，并比其单体肽更好地模拟gp41融合状态的生物活性构象。一种有效和化学选择性的连接策略已经被开发用于制备它们，使用不受保护的多肽作为单体来达到化学上明确的蛋白质模拟。初步结果有力地支持了我们方法的有效性。蛋白质模拟物在螺旋结构和抗蛋白质降解方面表现出显著的改善。更重要的是，几种药物在亚纳摩尔浓度下抑制HIV-1，其效力比T20强一个数量级，T20是一种多肽，也是第一种被批准的HIV-1进入抑制剂药物。我们的短期目标是继续模拟蛋白质的概念，增加设计元素，以提高效力、水溶解度和蛋白质分解阻力，并通过生化和生物物理方法确定它们的作用机制。由于在信号转导机制和1型包膜蛋白介导的病毒进入的蛋白质-蛋白质相互作用中发现了三聚螺旋线圈四级结构，我们的长期目标是提供一种结构驱动的方法来设计与人类疾病相关的蛋白质模拟抑制剂。