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）：本申请侧重于开发用于设计 HIV-1 进入抑制剂的蛋白质模拟概念。蛋白质模拟物是具有共价连接寡聚物的类蛋白质化合物，旨在模拟 gp41 三聚体卷曲前发夹的生物活性四级结构，并抑制其转变为通常参与病毒膜融合最后步骤的六螺旋束发夹。为了稳定其截短的寡聚螺旋结构，单体链在其氨基或羧基末端受到共价链间连接的约束，旨在赋予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。一种有效的化学选择性连接策略已被用于制备它们，使用未受保护的肽作为单体来获得化学上明确的蛋白质模拟物。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水解降解方面表现出显着改善。更重要的是，其中几种以亚纳摩尔浓度抑制 HIV-1，其效力比 T20（一种肽，也是第一个批准的 HIV-1 进入抑制剂药物）更有效一个数量级。我们的短期目标是延续蛋白质模拟概念，添加设计元素以提高效力、水溶性和蛋白水解抗性，并通过生物化学和生物物理方法确定其作用机制。由于三聚卷曲螺旋四级结构存在于信号传导机制的蛋白质-蛋白质相互作用和1型包膜蛋白介导的病毒进入中，因此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相关的蛋白质模拟抑制剂疾病。