RT Journal Article
SR Electronic
T1 Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.21.392753
DO 10.1101/2020.11.21.392753
A1 Kas Steuten
A1 Heeyoung Kim
A1 John C. Widen
A1 Brett M. Babin
A1 Ouma Onguka
A1 Scott Lovell
A1 Oguz Bolgi
A1 Berati Cerikan
A1 Mirko Cortese
A1 Ryan K. Muir
A1 John M. Bennett
A1 Ruth Geiss-Friedlander
A1 Christoph Peters
A1 Ralf Bartenschlager
A1 Matthew Bogyo
YR 2020
UL http://biorxiv.org/content/early/2020/11/23/2020.11.21.392753.abstract
AB Two proteases produced by the SARS-CoV-2 virus, Mpro and PLpro, 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 Mpro and PLpro proteases. These efforts identified a small number of hits for the Mpro protease and no viable hits for the PLpro protease. Of the Mpro 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 Mpro inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L and B and showed similar loss in activity in cells expressing TMPRSS2. Our results highlight the challenges of targeting Mpro and PLpro 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.Competing Interest StatementThe authors have declared no competing interest.