Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA.
Nat Commun. 2023 Mar 4;14(1):1237. doi: 10.1038/s41467-023-36569-y.
HIV-1 maturation inhibitors (MIs), Bevirimat (BVM) and its analogs interfere with the catalytic cleavage of spacer peptide 1 (SP1) from the capsid protein C-terminal domain (CA), by binding to and stabilizing the CA-SP1 region. MIs are under development as alternative drugs to augment current antiretroviral therapies. Although promising, their mechanism of action and associated virus resistance pathways remain poorly understood at the molecular, biochemical, and structural levels. We report atomic-resolution magic-angle-spinning NMR structures of microcrystalline assemblies of CA-SP1 complexed with BVM and/or the assembly cofactor inositol hexakisphosphate (IP6). Our results reveal a mechanism by which BVM disrupts maturation, tightening the 6-helix bundle pore and quenching the motions of SP1 and the simultaneously bound IP6. In addition, BVM-resistant SP1-A1V and SP1-V7A variants exhibit distinct conformational and binding characteristics. Taken together, our study provides a structural explanation for BVM resistance as well as guidance for the design of new MIs.
HIV-1 成熟抑制剂（MIs），如 Bevirimat（BVM）及其类似物，通过与衣壳蛋白 C 端结构域（CA）的 SP1 区域结合并稳定该区域，干扰间隔肽 1（SP1）从 CA 的催化裂解。MIs 正在开发中，作为辅助现有抗逆转录病毒疗法的替代药物。尽管前景广阔，但它们的作用机制以及相关的病毒耐药途径在分子、生化和结构水平上仍知之甚少。我们报告了 CA-SP1 与 BVM 和/或组装辅助因子肌醇六磷酸（IP6）复合的微晶组装的原子分辨率魔角旋转 NMR 结构。我们的结果揭示了 BVM 破坏成熟的机制，收紧了 6 螺旋束孔，并使 SP1 和同时结合的 IP6 的运动失活。此外，BVM 耐药的 SP1-A1V 和 SP1-V7A 变体表现出不同的构象和结合特征。总之，我们的研究为 BVM 耐药提供了结构解释，并为新型 MIs 的设计提供了指导。
