Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target
Wazir, Sarah; Parviainen, Tomi A. O.; Pfannenstiel, Jessica J.; Duong, Men Thi Hoai; Cluff, Daniel; Sowa, Sven T.; Galera-Prat, Albert; Ferraris, Dana; Maksimainen, Mirko M.; Fehr, Anthony R.; Heiskanen, Juha P.; Lehtiö, Lari (2024-04-09)
American chemical society
09.04.2024
Wazir, S., Parviainen, T. A. O., Pfannenstiel, J. J., Duong, M. T. H., Cluff, D., Sowa, S. T., Galera-Prat, A., Ferraris, D., Maksimainen, M. M., Fehr, A. R., Heiskanen, J. P., & Lehtiö, L. (2024). Discovery of 2-amide-3-methylester thiophenes that target sars-cov-2 mac1 and repress coronavirus replication, validating mac1 as an antiviral target. Journal of Medicinal Chemistry, 67(8), 6519–6536. https://doi.org/10.1021/acs.jmedchem.3c02451
https://rightsstatements.org/vocab/InC/1.0/
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of medicinal chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.3c02451.
https://rightsstatements.org/vocab/InC/1.0/
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of medicinal chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.3c02451.
https://rightsstatements.org/vocab/InC/1.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202404262980
https://urn.fi/URN:NBN:fi:oulu-202404262980
Tiivistelmä
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) had an IC50 of 2.1 μM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, 27 inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27. Compound 27 is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model.
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) had an IC50 of 2.1 μM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, 27 inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27. Compound 27 is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model.
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