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

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结合而启动的。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复合体与CCR5的结合启动了包膜糖蛋白的一系列构象变化，促进了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抑制剂的主要目标，被称为进入抑制剂。多项实验和L期临床试验结果表明，CCR5是发现新的进入抑制剂的有效靶点。由于目前还没有CCR5的三维结构，基于结构的设计目前还不可行。最近，我们从大量已报道的数据中确定了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以用于从大型类药物化学数据库中有效和快速地识别CCR5拮抗剂。鉴定这种抑制剂的具体目的是：(1)通过对大型数据库的虚拟筛选来鉴定与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试验来鉴定阻断gp120-CD4复合体与CCR5结合的先导HIV-1进入抑制剂；以及(3)设计和合成选定的聚焦文库。 总体而言，R21项目的这一阶段将提供新的先导化合物，作为潜在的艾滋病毒-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个最好的化合物进行进一步的临床前研究。

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.