Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment

Rana Abdelnabi, Dirk Jochmans, Kim Donckers, Bettina Trüeb, Nadine Ebert, Birgit Weynand, Volker Thiel and Johan Neyts ()
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Rana Abdelnabi: Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
Dirk Jochmans: Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
Kim Donckers: Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy
Bettina Trüeb: University of Bern
Nadine Ebert: University of Bern
Birgit Weynand: Division of Translational Cell and Tissue Research
Volker Thiel: University of Bern
Johan Neyts: Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy

Nature Communications, 2023, vol. 14, issue 1, 1-7

Abstract: Abstract The SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic targets for the treatment of COVID-19. Nirmatrelvir is the first 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization. We recently reported on the in vitro selection of SARS-CoV-2 3CLpro resistant virus (L50F-E166A-L167F; 3CLprores) that is cross-resistant with nirmatrelvir and other 3CLpro inhibitors. Here, we demonstrate that the 3CLprores virus replicates efficiently in the lungs of intranasally infected female Syrian hamsters and causes lung pathology comparable to that caused by the WT virus. Moreover, hamsters infected with 3CLprores virus transmit the virus efficiently to co-housed non-infected contact hamsters. Importantly, at a dose of 200 mg/kg (BID) of nirmatrelvir, the compound was still able to reduce the lung infectious virus titers of 3CLprores-infected hamsters by 1.4 log10 with a modest improvement in the lung histopathology as compared to the vehicle control. Fortunately, resistance to Nirmatrelvir does not readily develop in clinical setting. Yet, as we demonstrate, in case drug-resistant viruses emerge, they may spread easily which may thus impact therapeutic options. Therefore, the use of 3CLpro inhibitors in combination with other drugs may be considered, especially in immunodeficient patients, to avoid the development of drug-resistant viruses.

Date: 2023
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DOI: 10.1038/s41467-023-37773-6

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