Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir
Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans an...
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Nature Portfolio
2024-06-01
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| Series: | npj Viruses |
| Online Access: | https://doi.org/10.1038/s44298-024-00028-2 |
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| author | Laura Krismer Helge Schöppe Stefanie Rauch David Bante Bernhard Sprenger Andreas Naschberger Francesco Costacurta Anna Fürst Anna Sauerwein Bernhard Rupp Teresa Kaserer Dorothee von Laer Emmanuel Heilmann |
| author_facet | Laura Krismer Helge Schöppe Stefanie Rauch David Bante Bernhard Sprenger Andreas Naschberger Francesco Costacurta Anna Fürst Anna Sauerwein Bernhard Rupp Teresa Kaserer Dorothee von Laer Emmanuel Heilmann |
| author_sort | Laura Krismer |
| collection | DOAJ |
| description | Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35% and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of SARS-CoV-2, MERS-CoV and other main proteases. Nirmatrelvir inhibited several of these proteases, whereas ensitrelvir was less broadly active. To simulate nirmatrelvir’s clinical use against MERS-CoV and subsequent resistance development, we applied a safe, surrogate virus-based system. Using the surrogate virus, we previously selected hallmark mutations of SARS-CoV-2-Mpro, such as T21I, M49L, S144A, E166A/K/V and L167F. In the current study, we selected a pool of MERS-CoV-Mpro mutants, characterized the resistance and modelled the steric effect of catalytic site mutants S142G, S142R, S147Y and A171S. |
| format | Article |
| id | doaj-art-1322a7caaeab4ab2b156087e0d939fa6 |
| institution | OA Journals |
| issn | 2948-1767 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Viruses |
| spelling | doaj-art-1322a7caaeab4ab2b156087e0d939fa62025-08-20T01:57:25ZengNature Portfolionpj Viruses2948-17672024-06-012112010.1038/s44298-024-00028-2Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvirLaura Krismer0Helge Schöppe1Stefanie Rauch2David Bante3Bernhard Sprenger4Andreas Naschberger5Francesco Costacurta6Anna Fürst7Anna Sauerwein8Bernhard Rupp9Teresa Kaserer10Dorothee von Laer11Emmanuel Heilmann12Institute of Virology, Medical University of InnsbruckInstitute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of InnsbruckInstitute of Virology, Medical University of InnsbruckInstitute of Virology, Medical University of InnsbruckInstitute of Biochemistry, University of Innsbruck, CMBI – Center for Molecular Biosciences InnsbruckBiological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology KAUSTInstitute of Virology, Medical University of InnsbruckInstitute of Molecular Immunology, Technical University of MunichInstitute of Virology, Medical University of InnsbruckDivision of Genetic Epidemiology, Medical University of InnsbruckInstitute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of InnsbruckInstitute of Virology, Medical University of InnsbruckInstitute of Virology, Medical University of InnsbruckAbstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia in 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring the ability to efficiently spread among humans and become pandemic. Its high mortality rate of up to 35% and the absence of effective targeted therapies call for the development of antiviral drugs for this pathogen. Since the beginning of the SARS-CoV-2 pandemic, extensive research has focused on identifying protease inhibitors for the treatment of SARS-CoV-2. Our intention was therefore to assess whether these protease inhibitors are viable options for combating MERS-CoV. To that end, we used previously established protease assays to quantify inhibition of SARS-CoV-2, MERS-CoV and other main proteases. Nirmatrelvir inhibited several of these proteases, whereas ensitrelvir was less broadly active. To simulate nirmatrelvir’s clinical use against MERS-CoV and subsequent resistance development, we applied a safe, surrogate virus-based system. Using the surrogate virus, we previously selected hallmark mutations of SARS-CoV-2-Mpro, such as T21I, M49L, S144A, E166A/K/V and L167F. In the current study, we selected a pool of MERS-CoV-Mpro mutants, characterized the resistance and modelled the steric effect of catalytic site mutants S142G, S142R, S147Y and A171S.https://doi.org/10.1038/s44298-024-00028-2 |
| spellingShingle | Laura Krismer Helge Schöppe Stefanie Rauch David Bante Bernhard Sprenger Andreas Naschberger Francesco Costacurta Anna Fürst Anna Sauerwein Bernhard Rupp Teresa Kaserer Dorothee von Laer Emmanuel Heilmann Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir npj Viruses |
| title | Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir |
| title_full | Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir |
| title_fullStr | Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir |
| title_full_unstemmed | Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir |
| title_short | Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir |
| title_sort | study of key residues in mers cov and sars cov 2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir |
| url | https://doi.org/10.1038/s44298-024-00028-2 |
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