Department of Biology, Georgia State University, Atlanta, GA, 30303, USA.
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
Biochem Biophys Res Commun. 2019 Oct 29;519(1):61-66. doi: 10.1016/j.bbrc.2019.08.126. Epub 2019 Aug 29.
Drug-resistance threatens effective treatment of HIV/AIDS. Clinical inhibitors, including darunavir (1), are ineffective for highly resistant protease mutant PR20, however, antiviral compound 2 derived from 1 with fused tricyclic group at P2, extended amino-benzothiazole P2' ligand and two fluorine atoms on P1 shows 16-fold better inhibition of PR20 enzyme activity. Crystal structures of PR20 and wild-type PR complexes reveal how the extra groups of 2 counteract the expanded ligand-binding pocket, dynamic flaps, and faster dimer dissociation of PR20.
耐药性威胁着艾滋病的有效治疗。临床抑制剂，包括达芦那韦（1），对高度耐药的蛋白酶突变 PR20 无效，然而，源于 1 的抗病毒化合物 2 与 P2 融合的三环基团、延伸的氨基苯并噻唑 P2'配体和 P1 上的两个氟原子结合，对 PR20 酶活性的抑制作用提高了 16 倍。PR20 和野生型 PR 复合物的晶体结构揭示了 2 的额外基团如何对抗扩展的配体结合口袋、动态瓣和 PR20 的更快二聚体解离。
