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Volume 30, Number 6—June 2024
Research Letter

Sporadic Occurrence of Ensitrelvir-Resistant SARS-CoV-2, Japan

Akihiro Doi1, Masayuki Ota, Masumichi Saito, and Shutoku MatsuyamaComments to Author 
Author affiliation: National Institute of Infectious Diseases, Tokyo, Japan

Main Article

Table

Number of mutations in NSP5 causing ensitrelvir resistance during March 31–December 31, 2023, in study of sporadic occurrence of ensitrelvir-resistant SARS-CoV-2, Japan*

Amino acid substitutions‡ No. cases from GISAID database†
Globally Japan China United States Europe Others
T45I 25 0 1 4 15 (60.0) 5
D48Y 0 0 0 0 0 0
M49I 90 6 0 77 (85.6) 5 2
M49L 277 256 (92.4) 2 15 0 4
M49T 1 0 0 0 0 1
M49V 1 0 0 1 0 0
L50F 85 6 2 31 26 20
P52L 4 2 0 0 0 2
Y54C 0 0 0 0 0 0
S144A 4 2 0 0 1 1
E166A 1 1 0 0 0 0
E166V 23 0 1 4 10 8
L167F 0 0 0 0 0 0
P168del 4 0 0 0 0 4
A173T 23 0 1 6 11 5
A173V 23 2 0 6 3 12 (52.2)
Q192R 2 0 0 0 1 1

*Numbers in parentheses are percentages of total global cases (if a particular mutation was found in >10 cases and was responsible for >50% of global cases). del, deletion; NSP5, nonstructural protein 5. †Sequences were extracted from the GISAID EpiCoV database (https://www.gisaid.org). ‡Amino acid substitutions in NSP5 that trigger emergence of ensitrelvir-resistant SARS-CoV-2 (5–8).

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References
  1. Sasaki  M, Tabata  K, Kishimoto  M, Itakura  Y, Kobayashi  H, Ariizumi  T, et al. S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters. Sci Transl Med. 2023;15:eabq4064. DOIPubMedGoogle Scholar
  2. Kuroda  T, Nobori  H, Fukao  K, Baba  K, Matsumoto  K, Yoshida  S, et al. Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo. J Antimicrob Chemother. 2023;78:946–52. DOIPubMedGoogle Scholar
  3. Noske  GD, de Souza Silva  E, de Godoy  MO, Dolci  I, Fernandes  RS, Guido  RVC, et al. Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease. J Biol Chem. 2023;299:103004. DOIPubMedGoogle Scholar
  4. Japan Ministry of Health. Labour and Welfare. Usage of drugs for the treatment of novel coronavirus infections [cited 2023 Dec 31]. https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/0000121431_00324.html
  5. Kiso  M, Yamayoshi  S, Iida  S, Furusawa  Y, Hirata  Y, Uraki  R, et al. In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir. Nat Commun. 2023;14:4231. DOIPubMedGoogle Scholar
  6. Moghadasi  SA, Heilmann  E, Khalil  AM, Nnabuife  C, Kearns  FL, Ye  C, et al. Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors. Sci Adv. 2023;9:eade8778. DOIPubMedGoogle Scholar
  7. Jochmans  D, Liu  C, Donckers  K, Stoycheva  A, Boland  S, Stevens  SK, et al. The substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir. MBio. 2023;14:e0281522. DOIPubMedGoogle Scholar
  8. Flynn  JM, Huang  QYJ, Zvornicanin  SN, Schneider-Nachum  G, Shaqra  AM, Yilmaz  NK, et al. Systematic analyses of the resistance potential of drugs targeting SARS-CoV-2 main protease. ACS Infect Dis. 2023;9:1372–86. DOIPubMedGoogle Scholar
  9. Doi  A, Tomita  Y, Okura  H, Matsuyama  S. Frequent occurrence of mutations in nsp3 and nsp4 of SARS-CoV-2, presumably caused by the inhaled asthma drug ciclesonide. PNAS Nexus. 2022;1:pgac197.
  10. Japan National Institute of Infectious Diseases. Amino acid substitutions due to viral genomic mutations that may affect the efficacy of therapeutic drugs against the new coronavirus (SARS-CoV-2) (4th edition) [cited 2023 Dec 31]. https://www.niid.go.jp/niid/ja/2019-ncov/2624-flu/12170-sars-cov-2-mutation-v4.html

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1Current affiliation: ACEL Inc., Kanagawa, Japan.

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