HIV Fusion Inhibitors

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物概念。蛋白质模拟物是具有共价连接的寡聚体的蛋白质样化合物，其设计用于模拟gp 41三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的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限制，旨在赋予结构稳定性并比其单体肽更好地模拟gp 41的促融合状态的生物活性构象。一种有效的和化学选择性的连接策略已被开发用于其制备，使用未保护的肽作为单体，以达到化学上明确的蛋白质模拟物。初步结果有力地支持了我们的方法的有效性。蛋白质模拟物在螺旋结构和对蛋白水解降解的抗性方面表现出显著的改善。更重要的是，有几种抑制HIV-1的浓度低于纳摩尔浓度，比T20（一种肽）和第一种批准的HIV-1进入抑制剂药物更有效。我们的短期目标是继续蛋白质模拟的概念，增加设计元素，以增加效力，水溶性和蛋白水解抗性，并确定其作用机制的生物化学和生物物理方法。由于三聚体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，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。

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.