Potent and Biostable Inhibitors of the Main Protease of SARS-CoV-2

Overview

Journal iScience

Publisher Cell Press

Date 2022 Nov 7

PMID 36338434

Authors

Kohei Tsuji

Takahiro Ishii

Takuya Kobayakawa

Nobuyo Higashi-Kuwata

Chika Azuma

Miyuki Nakayama

Takato Onishi

Hiroki Nakano

Naoya Wada

Miki Hori

Kouki Shinohara

Yutaro Miura

Takuma Kawada

Hironori Hayashi

Shin-Ichiro Hattori

Haydar Bulut

Debananda Das

Nobutoki Takamune

Naoki Kishimoto

Junji Saruwatari

Tadashi Okamura

Kenta Nakano

Shogo Misumi

Hiroaki Mitsuya

Hirokazu Tamamura

Affiliations

Soon will be listed here.

Abstract

Potent and biostable inhibitors of the main protease (M) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of M and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound is highly potent and blocks SARS-CoV-2 infection without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds ( and ), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds and its biostable derivative are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Citing Articles

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