Design of inhibitors targeted to the CD4 binding site on HIV-1 gp120

项目总结/摘要 HIV-1包膜糖蛋白gp 120在介导病毒进入宿主细胞中起关键作用， 已被验证为小分子药物和疫苗开发的主要目标，但没有药物 迄今为止，gp 120已被美国食品和药物管理局（FDA）批准。因此有 迫切需要开发针对这一目标的新药。我们的团队在填补这一空白方面取得了重大进展， 通过开发针对HIV-1 gp 120的Phe 43空腔的一类新的HIV-1进入抑制剂来满足迫切的需求。 这一延长申请是在本供资周期内从 广泛的X射线结构、合成、以及抗病毒活性和毒性数据和体外ADMET 这类新型进入抑制剂的特征。新疗法的开发将有助于增加 可获得的新药和新药数量，特别是对于有治疗经验的患者， 治疗方案，并将扩大联合治疗的范围。这一高度协调的努力将进一步 我们的目标是开发有效的抑制剂，以便进入下一阶段的动物临床前评估， 用于选择两到三种抑制剂作为潜在的临床候选物。我们的长期目标是开发新颖， 高效、毒性较低的口服抗艾滋病毒药物，预计将成为新的组合药物库 治疗，特别是对于有治疗经验的患者。我们将通过解决四个高度问题来实现我们的目标。 协调的、假设驱动的具体目标：1.通过结构优化下一代HIV-1进入拮抗剂- 基础设计和综合药物化学。2.评价抗病毒效力、毒性、机制 和耐药性的影响。3.测量了键合热力学并确定了 具有（a）单体gp 120和（B）三聚体gp 120的最有效的进入抑制剂。4.评价体外 ADMET和实验室动物体内药代动力学（PK）。

Project Summary/Abstract The HIV-1 envelope glycoprotein gp120 plays a critical role in mediating viral entry into host cells and has been validated as a prime target for small-molecule drugs and vaccine development, yet no drugs against gp120 have been approved by the US Food and Drug Administration (FDA) to date. Therefore, there is a critical need to develop novel drugs against this target. Our group made significant headway in filling this critical need by developing a new class of HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120. This renewal application builds on the in-depth knowledge gained during the current funding cycle from the extensive X-ray structure, synthesis, as well as the antiviral activity and toxicity data and in vitro ADMET profiles of this class of novel entry inhibitor. The development of novel therapeutics will aid in increasing the number of new and novel drugs available, especially for the treatment-experienced patients, who have limited treatment options and will extend the scope of combination therapy. This highly coordinated effort will further our goal of developing potent inhibitors for moving to the next phase of preclinical assessments in animals and for selecting two to three inhibitors as potential clinical candidates. Our long-term goal is to develop novel, highly potent, and less toxic oral anti-HIV drugs, which are expected to serve as a new arsenal for combination therapy, especially for treatment-experienced patients. We will achieve our goals by addressing four highly coordinated, hypothesis-driven specific aims: 1. Optimize next-generation HIV-1 entry antagonists by structure- based design and comprehensive medicinal chemistry. 2. Evaluate the antiviral potency, toxicity, mechanism of action, and drug resistance. 3. Measure the binding thermodynamics and determine the X-ray structure of the most potent entry inhibitors with (a) monomeric gp120 and (b) trimeric gp120. 4. Evaluate the in vitro ADMET and in vivo pharmacokinetics (PK) in laboratory animals.