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Published on: May 24, 2020
In Vitro Selection and Characterization of Tecovirimat-resistant Mpox Virus
Kei Konishi1,2, Haruka Maeda1,2, Misato Shibazaki1,2
1Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan.
The Journal of Infectious Diseases
|May 18, 2026
Summary
Tecovirimat resistance in mpox virus (MPXV) can arise from VP37 mutations. Some mutations reduce drug susceptibility but maintain viral fitness, highlighting the need for diverse antiviral strategies.
Area of Science:
- Virology
- Antimicrobial Resistance
Background:
- Mpox virus (MPXV) causes mpox, a global health concern, with tecovirimat as a key antiviral.
- Emergence of tecovirimat-resistant MPXV strains with VP37 mutations is a growing challenge, especially in immunocompromised patients.
- The impact of specific VP37 mutations on tecovirimat susceptibility and viral fitness remains incompletely understood.
Purpose of the Study:
- To characterize the drug susceptibility and cellular fitness of MPXV variants with clinically observed VP37 mutations.
- To compare the impact of different VP37 substitutions on tecovirimat efficacy.
- To inform the development of novel antiviral therapies against resistant MPXV strains.
Main Methods:
- MPXV variants with VP37 substitutions were isolated in vitro under tecovirimat selective pressure.
- Drug susceptibility assays were performed to compare the efficacy of tecovirimat and brincidofovir against mutant viruses.
- Cellular fitness of the isolated MPXV mutants was evaluated in various human cell lines.
Main Results:
- VP37-N267D and -Y258C mutants displayed significantly reduced susceptibility to tecovirimat.
- VP37-I372N and -T245I (+I7L-A388S) mutants showed less impact on tecovirimat susceptibility.
- All tested VP37 mutants (I372N, T245I, Y258C, N267D) exhibited viral fitness comparable to the wild-type virus across multiple cell types.
- Mutant viruses retained susceptibility to brincidofovir, an alternative antiviral.
Conclusions:
- Specific VP37 mutations confer reduced susceptibility to tecovirimat while preserving viral fitness.
- The findings underscore the potential for tecovirimat-resistant MPXV to emerge and spread.
- Development of antivirals with distinct mechanisms of action is crucial for managing tecovirimat-resistant mpox infections.
