Chemical Screen Uncovers Novel Structural Classes of Inhibitors of the Papain-like Protease of Coronaviruses

Overview

Journal iScience

Publisher Cell Press

Date 2022 Oct 10

PMID 36213008

Authors

Kwiwan Jeong

Jinhee Kim

JuOae Chang

Subin Hong

Inseo Kim

Sunghyun Oh

Sangeun Jeon

Joo Chan Lee

Hyun-Ju Park

Seungtaek Kim

Wonsik Lee

Affiliations

Soon will be listed here.

Abstract

The papain-like protease (PLpro) of coronaviruses is an attractive antiviral target to inhibit both viral replication and interference of the host immune response. We have identified and characterized three novel classes of small molecules, thiophene, cyanofuran, and triazoloquinazoline, as PLpro inhibitors. Thiophene inhibited the PLpro of two major coronaviruses, Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) including SARS-CoV-2, while cyanofuran and triazoloquinazoline more selectively inhibited MERS-CoV PLpro. Unlike GRL0617, a known PLpro inhibitor, all three compounds contain no naphthyl group but like GRL0617 were predicted to fit on the cleft near the BL2 loop. Docking studies further revealed that the location and direction of the binding determined their specificity to different coronaviruses. Together, our work demonstrates that the BL2 loop and nearby regions are outstanding druggable targets, and our three inhibitors can be applicable to the development of therapeutics for coronavirus infection.

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