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）：人类免疫缺陷病毒 1 型（HIV-1）进入靶细胞是通过包膜糖蛋白表面单元 gpl20 与 CD4 和辅助受体（CXCR4 或 CCR5）的结合开始的，然后 gp41 从它的天然亚稳态构象到最终的融合活性热稳定构象。后一种构象是由三对 N 端和 C 端七肽重复序列（分别为 NHR 和 CHR）组成的六螺旋束。这种重折叠过程使病毒和靶细胞膜融合在一起。来自 CHR 区域的肽（称为 C 肽）能够与 gp41 NHR 区域结合，模拟六螺旋束中的相互作用，阻止融合活性 gp41 核心的形成，从而抑制 gp41 介导的膜融合。我们之前假设，与 gp41 NHR（尤其是空腔区域）结合的小分子可能会阻断 gp41 六螺旋束的形成并抑制 HIV-1 融合。这一假设通过 ADS-J1 的鉴定得到了验证，ADS-J1 是一种非肽 HIV-1 融合抑制剂，它特异性结合 gp41 NHR 区域中的“热点”，参与 gp41 重折叠过程中疏水空腔的形成并阻断融合。活跃的gp41核心形成。最近，我们发现了两种具有“类药物”特性的新型 N-取代吡咯衍生物，命名为 NB-2 和 NB-64。这两种化合物通过靶向 gp41 有效抑制 HIV-1 融合和复制，并可作为开发新型抗 HIV-1 疗法的先导化合物。我们假设，基于NB-2和NB-64的结构，通过先导化合物优化，可以设计出更有效的小分子HIV-1融合抑制剂作为抗HIV-1候选药物。该项目的具体目标是：1）基于先导化合物NB-2和NB-64的结构建立重点化学库； 2) 确定构效关系 (SAR)，以优化先导化合物并设计更有效的抗 HIV-1 化合物； 3）研究最活跃的HIV-1融合抑制剂的作用机制； 4) 评估所选化合物对具有不同基因型和表型的无细胞和细胞相关原代HIV-1毒株的体外感染的功效。长期目标是开发新型小分子HIV-1融合抑制剂作为一类新型抗HIV-1药物。