Peptide-to-Small Molecule: Discovery of Non-Covalent, Active-Site Inhibitors of β-Herpesvirus Proteases

  • ACS Med Chem Lett. 2023 Oct 27;14(11):1558-1566. doi: 10.1021/acsmedchemlett.3c00359.
Shuhei Yoshida  1 ,  Yusuke Sako  1 ,  Eiji Nikaido  1 ,  Taichi Ueda  1 ,  Iori Kozono  1 ,  Yusuke Ichihashi  1 ,  Atsufumi Nakahashi  1 ,  Motoyasu Onishi  1 ,  Yukiko Yamatsu  1 ,  Teruhisa Kato  1 ,  Junichi Nishikawa  2 ,  Yuki Tachibana  1
Affiliations
  • 1. Pharmaceutical Research Division, Shionogi Pharmaceutical Research Center, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
  • 2. PeptiDream Inc., 3-25-23 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan.
PMID: 37974946 DOI: 10.1021/acsmedchemlett.3c00359
Abstract

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 1 bound to the active site of human cytomegalovirus protease (HCMVPro) with high affinity, and pharmacophore queries were defined based on the results of subsequent intermolecular interaction analyses. Membrane-permeable small molecule 19, designed de novo according to this hypothesis, exhibited enzyme inhibitory activity (IC50 = 10-6 to 10-7 M) against β-herpesvirus proteases, and the design concept was proved by X-ray cocrystal analysis.