Pro108Ser mutation of SARS-CoV-2 3CL reduces the enzyme activity and ameliorates the clinical severity of COVID-19.

Makoto Ishii, Kenjiro Kosaki, Makoto Suematsu, Haruhiko Siomi, Masayuki Amagai, Koichi Fukunaga, Naoki Hasegawa, Mitsuru Murata, Masanori Noda, Takahiro Maruno, Toshiki Takenouchi, Shunsuke Uno, Yoshifumi Uwamino, Hirotsugu Ishizu, Yuka W Iwasaki, Susumu Uchiyama, Kodai Abe, Hideyuki Saya, Yasuaki Kabe, Yuko Kitagawa

Journal: Scientific reports 2022;12(1):1299

PMID: 35079088

Free Full Text on Nature Publishing Group View on PubMed

Abstract

Recently, an international randomized controlled clinical trial showed that patients with SARS-CoV-2 infection treated orally with the 3-chymotrypsin-like protease (3CL) inhibitor PF-07321332 within three days of symptom onset showed an 89% lower risk of COVID-19-related hospital admission/ death from any cause as compared with the patients who received placebo. Lending support to this critically important result of the aforementioned trial, we demonstrated in our study that patients infected with a SARS-Cov-2 sub-lineage (B.1.1.284) carrying the Pro108Ser mutation in 3CL tended to have a comparatively milder clinical course (i.e., a smaller proportion of patients required oxygen supplementation during the clinical course) than patients infected with the same sub-lineage of virus not carrying the mutation. Characterization of the mutant 3CL revealed that the Kcat/Km of the 3CL enzyme containing Ser108 was 58% lower than that of Pro108 3CL. Hydrogen/deuterium-exchange mass spectrometry (HDX-MS) revealed that the reduced activity was associated with structural perturbation surrounding the substrate-binding region of the enzyme, which is positioned behind and distant from the 108th amino acid residue. Our findings of the attenuated clinical course of COVID-19 in patients infected with SARS-CoV-2 strains with reduced 3CL enzymatic activity greatly endorses the promising result of the aforementioned clinical trial of the 3CL inhibitor.

Address: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.; Center for Medical Genetics, Keio University School of Medicine, 5 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.; Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.; Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka, Japan.; Exploratory Research Center On Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Japan.; Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan.; Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.; Division of Infection Diseases and Infection Control, Keio University Hospital, Tokyo, Japan.; Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan.; Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.; Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.; U-Medico, Inc., Osaka, Japan.; Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.; Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.; Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. [email protected].; Center for Medical Genetics, Keio University School of Medicine, 5 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. [email protected].

DOI: 10.1038/s41598-022-05424-3

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MeSH Terms: Adult, Aged, Amino Acid Substitution, COVID-19, Coronavirus 3C Proteases, Female, Humans, Male, Middle Aged, Mutation, Missense, Patient Acuity