Challenges for Targeting SARS-CoV‑2 Proteases as a Therapeutic Strategy for COVID-19
2021
academicJournal
Zugriff:
Two proteases produced by the SARS-CoV-2 virus, the main protease and papain-like protease, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both M pro and PL pro proteases. These efforts identified a small number of hits for the M pro protease and no viable hits for the PL pro protease. Of the M pro hits identified as inhibitors of the purified recombinant protease, only two compounds inhibited viral infectivity in cellular infection assays. However, we observed a substantial drop in antiviral potency upon expression of TMPRSS2, a transmembrane serine protease that acts in an alternative viral entry pathway to the lysosomal cathepsins. This loss of potency is explained by the fact that our lead M pro inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of M pro inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsins L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting M pro and PL pro proteases and demonstrate the need to carefully assess selectivity of SARS-CoV-2 protease inhibitors to prevent clinical advancement of compounds that function through inhibition of a redundant viral entry pathway.
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Challenges for Targeting SARS-CoV‑2 Proteases as a Therapeutic Strategy for COVID-19
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Autor/in / Beteiligte Person: | Kas Steuten (10104396) ; Heeyoung Kim (1987528) ; John C. Widen (1951051) ; Brett M. Babin (6184565) ; Ouma Onguka (10104399) ; Scott Lovell (122251) ; Oguz Bolgi (10104402) ; Berati Cerikan (6685166) ; Christopher J. Neufeldt (10104405) ; Mirko Cortese (296117) ; Ryan K. Muir (6551948) ; John M. Bennett (9217343) ; Ruth Geiss-Friedlander (6939698) ; Christoph Peters (207751) ; Ralf Bartenschlager (32666) ; Matthew Bogyo (178300) |
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Veröffentlichung: | 2021 |
Medientyp: | academicJournal |
DOI: | 10.1021/acsinfecdis.0c00815.s001 |
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