Yoshida Shuhei, Sako Yusuke, Nikaido Eiji, Ueda Taichi, Kozono Iori, Ichihashi Yusuke, Nakahashi Atsufumi, Onishi Motoyasu, Yamatsu Yukiko, Kato Teruhisa, Nishikawa Junichi, Tachibana Yuki
Pharmaceutical Research Division, Shionogi Pharmaceutical Research Center, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
PeptiDream Inc., 3-25-23 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan.
ACS Med Chem Lett. 2023 Oct 27;14(11):1558-1566. doi: 10.1021/acsmedchemlett.3c00359. eCollection 2023 Nov 9.
Viral proteases, the key enzymes that regulate viral replication and assembly, are promising targets for antiviral drug discovery. Herpesvirus proteases are enzymes with no crystallographically confirmed noncovalent active-site binders, owing to their shallow and polar substrate-binding pockets. Here, we applied our previously reported "Peptide-to-Small Molecule" strategy to generate novel inhibitors of β-herpesvirus proteases. Rapid selection with a display technology was used to identify macrocyclic peptide bound to the active site of human cytomegalovirus protease (HCMV) with high affinity, and pharmacophore queries were defined based on the results of subsequent intermolecular interaction analyses. Membrane-permeable small molecule , designed according to this hypothesis, exhibited enzyme inhibitory activity (IC = 10 to 10 M) against β-herpesvirus proteases, and the design concept was proved by X-ray cocrystal analysis.
病毒蛋白酶是调节病毒复制和组装的关键酶，是抗病毒药物研发的有前景的靶点。疱疹病毒蛋白酶由于其浅而极性的底物结合口袋，是没有晶体学确认的非共价活性位点结合剂的酶。在这里，我们应用我们先前报道的“肽到小分子”策略来生成新型β疱疹病毒蛋白酶抑制剂。使用展示技术进行快速筛选，以鉴定与人类巨细胞病毒蛋白酶（HCMV）活性位点高亲和力结合的大环肽，并根据随后的分子间相互作用分析结果定义药效团查询。根据这一假设设计的可透过膜的小分子对β疱疹病毒蛋白酶表现出酶抑制活性（IC = 10至10 M），并且通过X射线共晶体分析证明了设计概念。
