Xu Jimmy P, Francis Ashwanth C, Meuser Megan E, Mankowski Marie, Ptak Roger G, Rashad Adel A, Melikyan Gregory B, Cocklin Simon
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, USA.
Department of Pediatrics, Infectious Diseases, Emory University, USA.
J Drug Des Res. 2018;5(2). Epub 2018 Aug 13.
Recent efforts by both academic and pharmaceutical researchers have focused on the HIV-1 capsid (CA) protein as a new therapeutic target. An interprotomer pocket within the hexamer configuration of the CA, which is also a binding site for key host dependency factors, is the target of the most widely studied CA inhibitor compound PF-3450074 (PF-74). Despite its popularity, PF-74 suffers from properties that limit its usefulness as a lead, most notably it's extremely poor metabolic stability. To minimize unfavorable qualities, we investigated bioisosteric modification of the PF-74 scaffold as a first step in redeveloping this compound. Using a field-based bioisostere identification method, coupled with biochemical and biological assessment, we have created four new compounds that inhibit HIV-1 infection and that bind to the assembled CA hexamer. Detailed mechanism of action studies indicates that the modifications alter the manner in which these new compounds affect HIV-1 capsid core stability, as compared to the parental compound. Further investigations are underway to redevelop these compounds to optimize potency and drug-like characteristics and to deeply define the mechanism of action.
学术研究人员和制药研究人员最近都将重点放在了HIV-1衣壳（CA）蛋白上，将其作为一个新的治疗靶点。CA六聚体结构中的亚基间口袋，也是关键宿主依赖因子的结合位点，是研究最广泛的CA抑制剂化合物PF-3450074（PF-74）的作用靶点。尽管PF-74很受欢迎，但它存在一些特性限制了其作为先导化合物的实用性，最明显的是其代谢稳定性极差。为了尽量减少不利特性，我们研究了PF-74骨架的生物电子等排体修饰，作为重新开发该化合物的第一步。通过基于场的生物电子等排体识别方法，结合生化和生物学评估，我们制备了四种新化合物，它们能够抑制HIV-1感染并与组装好的CA六聚体结合。详细的作用机制研究表明，与母体化合物相比，这些修饰改变了这些新化合物影响HIV-1衣壳核心稳定性的方式。目前正在进行进一步研究，以重新开发这些化合物，优化其效力和类药特性，并深入确定其作用机制。
