Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.195
Analysis of SARS-CoV-2 Mutations after Nirmatrelvir Treatment in a Lung Cancer Xenograft Mouse Model
Bo Min Kang1,†, Dongbum Kim2,†, Jinsoo Kim2,†, Kyeongbin Baek1,†, Sangkyu Park3, Ha-Eun Shin3, Myeong-Heon Lee3, Minyoung Kim1, Suyeon Kim1, Younghee Lee3 and Hyung-Joo Kwon1,2,*
1Department of Microbiology, College of Medicine, Hallym University, Chuncheon 24252,
2Institute of Medical Science, College of Medicine, Hallym University, Chuncheon 24252,
3Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea
*E-mail: hjookwon@hallym.ac.kr
Tel: +82-33-248-2635, Fax: +82-33-241-3640
The first four authors contributed equally to this work.
Received: November 6, 2023; Revised: December 16, 2023; Accepted: December 18, 2023; Published online: June 5, 2024.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Paxlovid is the first approved oral treatment for coronavirus disease 2019 and includes nirmatrelvir, a protease inhibitor targeting the main protease (Mpro) of SARS-CoV-2, as one of the key components. While some specific mutations emerged in Mpro were revealed to significantly reduce viral susceptibility to nirmatrelvir in vitro, there is no report regarding resistance to nirmatrelvir in patients and animal models for SARS-CoV-2 infection yet. We recently developed xenograft tumors derived from Calu-3 cells in immunodeficient mice and demonstrated extended replication of SARS-CoV-2 in the tumors. In this study, we investigated the effect of nirmatrelvir administration on SARS-CoV-2 replication. Treatment with nirmatrelvir after virus infection significantly reduced the replication of the parental SARS-CoV-2 and SARS-CoV-2 Omicron at 5 days post-infection (dpi). However, the virus titers were completely recovered at the time points of 15 and 30 dpi. The virus genomes in the tumors at 30 dpi were analyzed to investigate whether nirmatrelvir-resistant mutant viruses had emerged during the extended replication of SARS-CoV-2. Various mutations in several genes including ORF1ab, ORF3a, ORF7a, ORF7b, ORF8, and N occurred in the SARS-CoV-2 genome; however, no mutations were induced in the Mpro sequence by a single round of nirmatrelvir treatment, and none were observed even after two rounds of treatment. The parental SARS-CoV-2 and its sublineage isolates showed similar IC50 values of nirmatrelvir in Vero E6 cells. Therefore, it is probable that inducing viral resistance to nirmatrelvir in vivo is challenging differently from in vitro passage.
Keywords: COVID-19, Drug resistance, Long-term infection model, Nirmatrelvir, SARS-CoV-2


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