Rational Design of CCR5 Antagonists as Anti-HIV-1 Drugs

CCR5 拮抗剂作为抗 HIV-1 药物的合理设计

• 批准号: 6891780
• 负责人: Asim K Debnath
• 金额: $ 20.77万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891780
• 关键词: AIDS therapy; CD4 molecule; HIV envelope protein gp120; antiAIDS agent; binding sites; chemical structure function; cheminformatics; chemokine receptor; combinatorial chemistry; conformation; drug design /synthesis /production; drug discovery /isolation; drug receptors; drug screening /evaluation; enzyme linked immunosorbent assay; host organism interaction; human tissue; immunopathology chemotherapy; inhibitor /antagonist; microorganism disease chemotherapy; small molecule; virus infection mechanism; virus receptors

DESCRIPTION (provided by applicant): Human immunodeficiency virus type 1 (HIV-1) infection is initiated by binding of the virus envelope glycoprotein gp120 with the primary cellular receptor CD4. This interaction creates a high affinity binding site (CD4i) on gp120 for the chemokine receptor (CXCR4 or CCR5), designated as coreceptor. CCR5 is a G protein coupled receptor (GPCR) and the principal coreceptor used during natural infection and transmission of HIV-1, including sexual transmission. The binding of the gp120-CD4 complex to CCR5 initiates a series of conformational changes in the envelope glycoprotein and facilitates HIV-1 fusion to the target cells. Therefore, the initial events of the HIV-1 infection process have been a major target for developing new classes of HIV-1 inhibitors, named as entry inhibitors. Several experiments and Phase l/ll clinical trial results indicate that CCR5 is a valid target for discovery of new entry inhibitors. Since there is no three-dimensional structure of CCR5 available, structure-based design is not feasible at this time. Recently, we have identified, from a large set of reported data, important features (pharmacophore models) for CCR5 antagonists. We hypothesize that the pharmacophore based models can be used to effectively and rapidly identify CCR5 antagonists from large drug-like chemical databases. The specific aims to accomplish the objective of identifying such inhibitors are: (1) to identify small molecule organic lead compounds that bind to CCR5 by virtual screening of large databases; (2) to identify lead HIV-1 entry inhibitors that block binding of the gp120-CD4 complex to CCR5 by biochemical and virological screening assays; and (3) To design and synthesize a selected focused library. Overall, this phase of the R21 project will provide new lead compounds that act as potential HIV-1 entry inhibitors. The long term goal is to optimize the lead compounds through chemical syntheses and structure activity relationship (SAR) analyses and select the 3-4 best compounds for further preclinical studies.

描述（由申请人提供）： 1 型人类免疫缺陷病毒 (HIV-1) 感染是通过病毒包膜糖蛋白 gp120 与初级细胞受体 CD4 的结合引发的。这种相互作用在 gp120 上为趋化因子受体（CXCR4 或 CCR5）创建了一个高亲和力结合位点 (CD4i)，称为辅助受体。 CCR5 是一种 G 蛋白偶联受体 (GPCR)，是 HIV-1 自然感染和传播（包括性传播）过程中使用的主要辅助受体。 gp120-CD4 复合物与 CCR5 的结合引发了包膜糖蛋白的一系列构象变化，并促进 HIV-1 与靶细胞的融合。因此，HIV-1感染过程的初始事件一直是开发新型HIV-1抑制剂（称为进入抑制剂）的主要目标。多项实验和 I/II 期临床试验结果表明，CCR5 是发现新进入抑制剂的有效靶点。由于CCR5没有可用的三维结构，因此基于结构的设计目前不可行。最近，我们从大量报告数据中确定了 CCR5 拮抗剂的重要特征（药效团模型）。我们假设基于药效团的模型可用于从大型类药物化学数据库中有效、快速地识别 CCR5 拮抗剂。实现识别此类抑制剂的具体目标是：（1）通过大型数据库的虚拟筛选来识别与CCR5结合的小分子有机先导化合物； (2) 通过生化和病毒学筛选测定来鉴定阻断 gp120-CD4 复合物与 CCR5 结合的主要 HIV-1 进入抑制剂； (3) 设计和合成选定的重点库。 总体而言，R21 项目的这一阶段将提供新的先导化合物，作为潜在的 HIV-1 进入抑制剂。长期目标是通过化学合成和构效关系（SAR）分析来优化先导化合物，并选择3-4个最佳化合物进行进一步的临床前研究。