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）：人类免疫缺陷病毒1型（HIV-1）感染是通过病毒包膜糖蛋白GP120与主要细胞受体CD4结合而引发的。这种相互作用在GP120上为趋化因子受体（CXCR4或CCR5）创建了高亲和力结合位点（CD4I），该趋化因子受体被指定为共肽。 CCR5是G蛋白偶联受体（GPCR），也是HIV-1的自然感染和传播过程中使用的主要共肽，包括性传播。 GP120-CD4复合物与CCR5的结合启动了包膜糖蛋白的一系列构象变化，并促进HIV-1融合到靶细胞上。因此，HIV-1感染过程的最初事件一直是开发新类别的HIV-1抑制剂（称为进入抑制剂）的主要目标。几个实验和LL/LL临床试验结果表明，CCR5是发现新进入抑制剂的有效目标。由于CCR5没有三维结构，因此目前基于结构的设计是不可行的。最近，我们从CCR5拮抗剂的大量报告的数据，重要特征（药效团模型）中确定了。我们假设基于药效团的模型可用于从大型药物样化学数据库中有效，迅速鉴定CCR5拮抗剂。实现鉴定这种抑制剂目标的具体目的是：（1）通过虚拟筛选大型数据库来识别与CCR5结合的小分子有机铅化合物； （2）通过生化和病毒学筛选测定法确定铅HIV-1进入抑制剂，以阻断GP120-CD4复合物与CCR5的结合； （3）设计和合成选定的集中库。 总体而言，R21项目的这一阶段将提供新的铅化合物，可作为潜在的HIV-1进入抑制剂。长期目标是通过化学合成和结构活动关系（SAR）分析来优化铅化合物，并选择3-4种最佳化合物以进行进一步的临床前研究。