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Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
| Content Provider | MDPI |
|---|---|
| Author | Pavla, Fajtová O’donoghue, Anthony J. Meewan, Ittipat Kattoula, Jacob Kattoula, Julius Y. Skinner, Danielle Giardini, Miriam A. Woodworth, Brendon McKerrow, James H. de Siqueira-Neto, Jair Lage Abagyan, Ruben |
| Copyright Year | 2022 |
| Description | One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with $IC_{50}$s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants. |
| Starting Page | 744 |
| e-ISSN | 14248247 |
| DOI | 10.3390/ph15060744 |
| Journal | Pharmaceuticals |
| Issue Number | 6 |
| Volume Number | 15 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-06-13 |
| Access Restriction | Open |
| Subject Keyword | Pharmaceuticals Medicinal Chemistry Covid-19 Drug Candidates Multiple Protease Inhibitors Disulfiram Thiuram Disulfide Dithiobis-(thioformate) Sars-cov-2 Main Protease Sars-cov-2 Papain-like Protease Cathepsin L Transmembrane Serine Protease 2 Tmprss2 Covid-19 |
| Content Type | Text |
| Resource Type | Article |
