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

作为 HIV-1 进入抑制剂的新型二胺衍生物的发现和优化

• 批准号: 8603526
• 负责人: Simon Cocklin
• 金额: $ 21.46万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603526
• 关键词: Affinity; Anti-HIV Agents; Antibodies; Antiviral Agents; Binding; Binding Sites; Biological; Biological Assay; Biological Testing; CCR5 gene; CXCR4 gene; Cell Surface Receptors; Cell membrane; Cells; Chemicals; Chemistry; Chemokine (C-C Motif) Receptor 5; Clinic; Collaborations; Computer Assisted; Computer Simulation; Contracts; Development; Diamines; Dissection; Doctor of Philosophy; Drug Design; Electrons; Event; Exhibits; Fuzeon; Generations; Glycoproteins; Goals; Group Identifications; HIV; HIV Envelope Protein gp120; HIV-1; Halogens; In Vitro; Infection; Inhibitory Concentration 50; Interdisciplinary Study; Investigation; Knowledge; Laboratories; Lead; Maps; Molecular; Molecular Conformation; Murine leukemia virus; New York; Pharmaceutical Chemistry; Pharmaceutical Preparations; Piperazines; Process; Property; Proteins; Quantitative Structure-Activity Relationship; Reagent; Recombinants; Series; Services; Site; Solubility; Specificity; Structure; Structure-Activity Relationship; Surface; Surface Plasmon Resonance; System; T-20; Testing; Therapeutic Index; Toxic effect; Training; Trees; Variant; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Replication; analog; base; chemical synthesis; chemokine; design; experience; flexibility; improved; inhibitor/antagonist; innovation; interdisciplinary approach; mutant; novel; pharmacophore; public health relevance; pyridine; receptor; receptor binding; recombinant virus; scaffold; screening; small molecule; success; virus envelope

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.

描述：这项建议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。这一最初的结合事件导致了一系列变构事件，从联合受体的激活，随后与趋化因子联合受体(CCR5或CXCR4)的结合，gp41的融合构象，最后病毒和细胞膜的融合。由于进入过程是病毒复制的关键，它是寻找治疗艾滋病毒-1感染的新药的最重要目标之一。对HIV-1进入的分子机制的了解的进展使阻止进入过程的每一步的分子得以发现和发展，并已成功地用于临床，例如马拉韦罗(Selzentry，Pfizer，纽约，纽约)和恩富韦肽(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。使用一种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。通过生物等位取代化合物中的一个中心哌嗪和一个庚基团，得到了化合物SC08--一种具有新的化学型和亚微摩尔效力的新型进入抑制剂。我们将把药物化学与计算机辅助药物设计(CADD)以及有效性、选择性和毒性的生物测试结合起来。我们的方法集成了高含量的药效团作图和三维定量结构-活性关系、化学合成、使用重组野生型和突变型HIV gp120变体的直接结合分析，以及使用来自不同基因的初级HIV分离株的伪型病毒的单轮感染分析。化合物的毒性将使用未感染的PBMCs以及293T和U87细胞进行测试，以评估治疗指数。该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，最终可能扩大抗HIV武器。