Rational Design of HIV Fusion Inhibitors Targeting gp41

针对 gp41 的 HIV 融合抑制剂的合理设计

• 批准号: 6842727
• 负责人: SHIBO JIANG
• 金额: $ 31.22万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842727
• 关键词: HIV envelope protein gp41; X ray crystallography; analog; antiAIDS agent; chemical structure function; combinatorial chemistry; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; genotype; human immunodeficiency virus 1; human tissue; laboratory mouse; membrane fusion; monoclonal antibody; pharmacokinetics; phenotype; small molecule

DESCRIPTION (provided by applicant): Entry of the human immunodeficiency virus type 1 (HIV-1) into the target cell is initiated by binding of the envelope glycoprotein surface unit gpl20 to CD4 and a coreceptor (CXCR4 or CCR5) followed by gp41 refolding from its native, metastable conformation to a final fusion-active, thermostable conformation. The latter conformation is a six-helix bundle consisting of three pairs of the N- and C-terminal heptad repeats (NHR and CHR, respectively). This refolding process brings the viral and target cell membranes together for fusion. Peptides derived from CHR region, named C-peptides, are able to bind to the gp41 NHR region, mimicking interactions in the six-helix bundle, to block formation of the fusion-active gp41 core, thereby inhibiting gp41-mediated membrane fusion. We previously hypothesized that a small molecule that binds to the gp41 NHR, especially the cavity region, may block the gp41 six-helix bundle formation and inhibit HIV-1 fusion. This hypothesis was validated by identification of ADS-J1, a non-peptide HIV-1 fusion inhibitor which specifically binds to a "hot spot" in the gp41 NHR region that participates in formation of a hydrophobic cavity during gp41 refolding and blocks the fusion-active gp41 core formation. Most recently, we identified two novel N-substituted pyrrole derivatives with "drug-like" properties, designated NB-2 and NB-64. These two compounds effectively inhibited HIV-1 fusion and replication by targeting gp41 and may serve as leads for developing novel anti-HIV-1 therapeutics. We hypothesize that more potent small molecule HIV-1 fusion inhibitors as anti-HIV-1 drug candidates can be designed based on the structures of NB-2 and NB-64 by lead optimization. The specific aims of this project are: 1) to establish a focused chemical library based on the structures of the lead compounds NB-2 and NB-64; 2) To determine the structure-activity relationship (SAR) for lead optimization and for designing more potent anti-HIV-1 compounds; 3) to study the mechanism of action of the most active HIV-1 fusion inhibitors; and 4) to evaluate the efficacy of the selected compounds on in vitro infection by cell-free and cell-associated primary HIV-1 strains with distinct genotypes and phenotypes. The long-term goal is to develop novel small molecule HIV-1 fusion inhibitors as a new class of anti-HIV-1 drugs.

描述（由申请人提供）：通过包膜糖蛋白表面GPL20与CD4与CD4的结合和共核能（CXCR4或CCR5）的结合，将人类免疫缺陷病毒型（HIV-1）输入到靶细胞中，从而启动，然后由GP41从其天然构象中重新构成，然后将其本机构象从最终的构象中重新构成，以最终的质感与最终的效果相同。后一种构象是一个六螺旋束，由三对n-和c末端的七个重复序列（分别为NHR和CHR）组成。这种重折叠过程将病毒和靶细胞膜融合在一起以进行融合。从ChR区（称为C肽）衍生的肽能够与GP41 NHR区域结合，模仿六螺旋束中的相互作用，以阻止融合活性GP41核的形成，从而抑制GP41介导的膜介导的膜融合。我们先前假设，与GP41 NHR结合的小分子，尤其是腔区域，可能会阻断GP41六螺旋束的形成并抑制HIV-1融合。通过鉴定ADS-J1（一种非肽HIV-1融合抑制剂ADS-J1）与GP41 NHR区域中特异性结合的ADS-J1鉴定来验证该假设，该抑制剂特异性地结合了GP41 NHR区域中的“热点”，该抑制剂参与GP41重折叠过程中疏水腔的形成并阻止融合活性GP41核心形成。最近，我们确定了两个新型的N-取代的吡咯衍生物，具有“药物样”特性，分别为NB-2和NB-64。这两种化合物通过靶向GP41有效地抑制了HIV-1融合和复制，并可以作为开发新型抗HIV-1治疗剂的铅。我们假设可以通过铅优化基于NB-2和NB-64的结构来设计更有效的小分子HIV-1融合抑制剂作为抗HIV-1药物候选者。该项目的具体目的是：1）基于铅化合物NB-2和NB-64的结构建立重点化学库； 2）确定铅优化和设计更有效的抗HIV-1化合物的结构活性关系（SAR）； 3）研究最活跃的HIV-1融合抑制剂的作用机理； 4）评估所选化合物对具有不同基因型和表型的无细胞和相关的原代HIV-1菌株对体外感染的疗效。长期目标是将新型的小分子HIV-1融合抑制剂作为一种新的抗HIV-1药物。