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01 25, 2022;12 (1): 1299.

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

Kodai Abe, Yasuaki Kabe, Susumu Uchiyama, Yuka W Iwasaki, Hirotsugu Ishizu, Yoshifumi Uwamino, Toshiki Takenouchi, Shunsuke Uno, Makoto Ishii, Takahiro Maruno, Masanori Noda, Mitsuru Murata, Naoki Hasegawa, Hideyuki Saya, Yuko Kitagawa, Koichi Fukunaga, Masayuki Amagai, Haruhiko Siomi, Makoto Suematsu, Kenjiro Kosaki, Keio Donner Project
Author Information
  1. Kodai Abe: Department of Surgery, Keio University School of Medicine, Tokyo, Japan. ORCID
  2. Yasuaki Kabe: Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. ORCID
  3. Susumu Uchiyama: Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka, Japan. ORCID
  4. Yuka W Iwasaki: Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan. ORCID
  5. Hirotsugu Ishizu: Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.
  6. Yoshifumi Uwamino: Division of Infection Diseases and Infection Control, Keio University Hospital, Tokyo, Japan.
  7. Toshiki Takenouchi: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. ORCID
  8. Shunsuke Uno: Division of Infection Diseases and Infection Control, Keio University Hospital, Tokyo, Japan.
  9. Makoto Ishii: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
  10. Takahiro Maruno: Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka, Japan.
  11. Masanori Noda: U-Medico, Inc., Osaka, Japan.
  12. Mitsuru Murata: Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
  13. Naoki Hasegawa: Division of Infection Diseases and Infection Control, Keio University Hospital, Tokyo, Japan.
  14. Hideyuki Saya: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. ORCID
  15. Yuko Kitagawa: Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
  16. Koichi Fukunaga: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
  17. Masayuki Amagai: Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
  18. Haruhiko Siomi: Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan.
  19. Makoto Suematsu: Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan. gasbiology@keio.jp. ORCID
  20. Kenjiro Kosaki: Center for Medical Genetics, Keio University School of Medicine, 5 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. kkosaki@keio.jp.
PMID: 35079088 DOI: 10.1038/s41598-022-05424-3

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.

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MeSH Term

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

Chemicals

3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 3

Word Cloud

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