Structural Analysis of HIV-1 Viral Entry Inhibitors

描述（由申请人提供）：世界卫生组织估计，超过4000万人感染艾滋病毒/艾滋病。对目前抗逆转录病毒治疗的新出现的耐药性突出了开发针对传统靶点（蛋白酶或逆转录酶）以外的靶点的新药的必要性。在新的药物类别中，HIV病毒进入抑制剂特别有前途，因为它们靶向参与病毒膜融合的蛋白质复合物。BMS-806是一种与HIV-1包膜蛋白gp 120结合的小分子候选药物，已被证明是一种有效和特异性的HIV-1病毒进入抑制剂。尽管已经在临床试验中，但仍然缺乏对BMS-806及其类似物作用机制的完整理解。该提案旨在从根本上了解BMS- 806与包膜糖蛋白gp 120结合的分子机制，以确定其抗病毒活性的化学和结构决定因素。这些研究将为设计新的小分子支架提供基础信息，这些支架包含抑制病毒进入的基本结合特征。病毒进入抑制剂的混合物的产生将减缓耐药性的发生。

DESCRIPTION (provided by applicant): The World Health Organization estimates that over 40 million people are infected with HIV/AIDS. Emerging resistance to current antiretroviral treatments accentuates the need for the developing of new drugs aimed at targets other than the traditional ones, protease or reverse transcriptase. Among the new classes of drugs, the HIV viral entry inhibitors are especially promising since they target protein complexes involved in viral membrane fusion. BMS-806, a small molecule drug candidate that binds to the HIV-1 envelope protein gp120, has shown to be a potent and specific HIV-1 viral entry inhibitor. Despite being already in clinical trials, a complete understanding of the mechanism of action of BMS-806 and its analogs is still lacking. This proposal is designed to gain a fundamental understanding of the molecular mechanism of binding of BMS- 806 to the envelope glycoprotein gp120 in order to identify the chemical and structural determinants of its antiviral activity. The proposed studies will provide fundamental information for the design of new small molecule scaffolds that contain the essential binding characteristics for viral entry inhibition. The creation of a cocktail of viral entry inhibitors will slow down the onset of drug resistance.