| Autor: |
Martin A. Redhead, C. David Owen, Lennart Brewitz, Amelia H. Collette, Petra Lukacik, Claire Strain-Damerell, Sean W. Robinson, Patrick M. Collins, Philipp Schäfer, Mark Swindells, Chris J. Radoux, Iva Navratilova Hopkins, Daren Fearon, Alice Douangamath, Frank von Delft, Tika R. Malla, Laura Vangeel, Thomas Vercruysse, Jan Thibaut, Pieter Leyssen, Tu-Trinh Nguyen, Mitchell Hull, Anthony Tumber, David J. Hallett, Christopher J. Schofield, David I. Stuart, Andrew L. Hopkins, Martin A. Walsh |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Scientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2045-2322 |
| DOI: |
10.1038/s41598-021-92416-4 |
| Popis: |
Abstract Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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