Combinatorial Chemistry for HIV Entry Inhibitors

描述（由申请人提供）：我们建议使用组合化学方法来鉴定HIV-1进入细胞的新型抑制剂。我们最初的重点是开发潜在的抗病毒杀微生物剂来防止传播，但这种方法将产生对艾滋病治疗也有用的药物。迫切需要开发新的和有效的抗HIV治疗剂。目前用于HIV感染者的高效抗逆转录病毒疗法（HAART）针对病毒蛋白酶和逆转录酶。然而，HAARRT的局限性是毒性、患者依从性和耐药病毒突变体的出现。因此，需要新的抗病毒剂来规避这些严重的限制。在这个项目中，我们使用了主要由D-氨基酸或其他小分子组成的组合肽库。我们的重点是开发针对HIV-1包膜糖蛋白（gp 120）和跨膜亚基（gp 41）内结构域的进入和/或附着抑制剂。在初步研究中，我们筛选了主要由D-氨基酸构建的肽库，并鉴定了许多与纯化的HIV-I寡聚gp 140结合的肽库。这些化合物之一抑制HIV-1复制，50%抑制浓度（EC 50）为8 μ/M。该项目的近期目标是：1）通过筛选额外的库来识别几种额外的进入抑制剂，2）优化这些针对包膜糖蛋白的最有前途的抑制剂的抗病毒活性，以及3）表征抗病毒活性和病毒耐药性的机制。未来的计划是在我们的SHIV/恒河猴模型中测试粘膜传播和艾滋病的药物和策略。

DESCRIPTION (provided by applicant): We propose to use a combinatorial chemistry approach to identify novel inhibitors of HIV-1 entry into cells. Our initial focus is on development of potential antiviral microbicides to prevent transmission, but this approach will yield agents that should also be useful for AIDS therapy. There is an urgent need for the development of novel and effective anti-HIV therapeutic agents. Current highly active antiretroviral therapy (HAART) for HIV-infected individuals is targeted against the viral protease and reverse transcriptase. However, limitations of HAARRT are toxicity, patient compliance and emergence of drug-resistant virus mutants. Accordingly, novel antiviral agents are needed to circumvent these serious limitations. For this project we are using combinatorial peptide libraries that consist primarily of D-amino acids or other small molecules. Our focus is on development of entry and/or attachment inhibitors that are targeted against HIV-1 envelope glycoprotein (gp120) and domains within the transmembrane subunit (gp41). In preliminary studies we have screened peptide libraries that were constructed predominantly with D-amino acids, and have identified many that bind to purified oligomerized gp140 of HIV-I. One of these compounds inhibits HIV-1 replication with a 50% inhibitory concentration (EC50) of 8 mu/M. Immediate goals of this project are: 1) to identify several additional entry inhibitors by screening of additional libraries, 2) to optimize the antiviral activity of the most promising of these inhibitors targeted to the envelope glycoprotein, and 3) to characterize mechanism(s) of antiviral activity and viral drug-resistance. Future plans are to test the drugs and strategies in our SHIV/rhesus macaque models for mucosal membrane transmission and AIDS.