Discovery and optimization of novel diamine derivatives as HIV-1 entry inhibitors

描述：本提案的目标是优化新发现的HIV-1进入抑制剂并阐明其广泛的作用机制。当包膜糖蛋白gp120与细胞表面受体CD4结合时，HIV-1感染开始。这一初始结合事件导致一系列变构事件，包括共受体位点的激活，随后与趋化因子共受体（CCR5或CXCR4）的结合，gp41的融合构象，以及病毒和细胞膜的最终融合。由于进入过程是病毒复制的关键，因此它是寻找治疗HIV-1感染新药的最重要靶点之一。随着对HIV-1进入的分子机制的了解的进步，可以发现和开发阻断进入过程的每个步骤的分子，并已成功地用于临床，例如，maraviroc （Selzentry, Pfizer, New York， NY）和enfuvirtide （Fuzeon, Hoffman-La Roche, Nutley， NJ）。然而，到目前为止，还没有gp120靶向疗法被批准用于临床。使用创新的高含量药效团方法，我们发现了SC03，一种新的进入抑制剂，在单轮感染试验中显示出微摩尔效力。该化合物的中心哌嗪和苊部分的生物等构取代导致化合物SC08 -一种具有新化学型和亚微摩尔效价的新型进入抑制剂。我们将结合药物化学与计算机辅助药物设计（CADD）和效价、选择性和毒性的生物测试。我们的方法整合了高含量药效团定位和三维定量结构-活性关系，化学合成，使用重组野生型和突变型HIV gp120变体的直接结合测定，以及使用基因不同的原发HIV分离株的病毒假型包膜的单轮感染测定。化合物的毒性将使用未感染的pbmc以及293T和U87细胞进行测试，以评估治疗指数。这个项目的成功将提供新的有效的和选择性的HIV-1进入抑制剂，可能最终扩大抗hiv武器。

DESCRIPTION: The goal of this proposal is the optimization of newly discovered HIV-1 entry inhibitors and elucidation of their broad mechanism of action. HIV-1 infection begins when the envelope glycoprotein gp120 binds to the cell surface receptor CD4. This initial binding event results in a series of allosteric events from activation of the co- receptor site, subsequent binding to the chemokine co-receptor (CCR5 or CXCR4), fusogenic conformation of gp41, and finally fusion of the viral and cell membranes. As the process of entry is key to the replication o the virus, it is one of the most important targets in the search for new drugs to treat HIV-1 infection. Advances in knowledge of the molecular mechanisms of HIV-1 entry have allowed the discovery and development of molecules that block each step of the entry process and that have been successfully used in the clinic, e.g., maraviroc (Selzentry, Pfizer, New York, NY) and enfuvirtide (Fuzeon, Hoffman-La Roche, Nutley, NJ). To date, however, no gp120-targeted therapies have been approved for use in the clinic. Using an innovative high- content pharmacophore approach, we have discovered SC03, a new entry inhibitor that shows micromolar potency in a single-round infection assay. Bioisosteric replacement of a central piperazine and an acenaphthene moiety in this compound has led to the identification of compound SC08 - a novel entry inhibitor with a new chemotype and sub-micromolar potency. We will combine medicinal chemistry with computer-aided drug design (CADD) and biological testing for potency, selectivity, and toxicity. Our approach integrates high- content pharmacophore mapping and three-dimensional quantitative structure-activity relationships, chemical synthesis, direct binding assays using recombinant wild-type and mutant HIV gp120 variants, and single-round infection assays using virus pseudotyped with envelopes from genetically disparate primary HIV isolates. The toxicity of compounds will be tested using uninfected PBMCs as well as 293T and U87 cells to assess therapeutic index. The success of this project will provide novel potent and selective HIV-1 entry inhibitors that may ultimately expand the anti-HIV armamentarium.