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

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. Her...

Full description

Saved in:
Bibliographic Details
Published in:ACS medicinal chemistry letters 2023-11, Vol.14 (11), p.1558-1566
Main Authors: Yoshida, Shuhei, Sako, Yusuke, Nikaido, Eiji, Ueda, Taichi, Kozono, Iori, Ichihashi, Yusuke, Nakahashi, Atsufumi, Onishi, Motoyasu, Yamatsu, Yukiko, Kato, Teruhisa, Nishikawa, Junichi, Tachibana, Yuki
Format: Article
Language:English
Subjects:
Letter
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.3c00359