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）感染是由病毒包膜糖蛋白gp120与原代细胞受体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）创建了一个高亲和力的结合位点（CD4i），被指定为辅助受体。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，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（称为进入抑制剂）的主要目标。一些实验和i /ll期临床试验结果表明，CCR5是发现新进入抑制剂的有效靶点。由于目前没有CCR5的三维结构，因此基于结构的设计目前是不可行的。最近，我们从大量报道的数据中发现了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药物样化学数据库中有效快速地识别CCR5拮抗剂。鉴定此类抑制剂的具体目标是：(1)通过大型数据库的虚拟筛选，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鉴定阻断gp120-CD4复合物与CCR5结合的HIV-1进入抑制剂；(3)设计和合成选定的聚焦库。

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.