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MeSH Disease

COVID-19 (1)


HGNC Genes

SARS-CoV-2 proteins

NSP5 (1)

NSP3 (1)


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    Challenges for targeting SARS-CoV-2 proteases as a therapeutic strategy for COVID-19 MESHD

    Authors: Kas Steuten; Heeyoung Kim; John C. Widen; Brett M. Babin; Ouma Onguka; Scott Lovell; Oguz Bolgi; Berati Cerikan; Mirko Cortese; Ryan K. Muir; John M. Bennett; Ruth Geiss-Friedlander; Christoph Peters; Ralf Bartenschlager; Matthew Bogyo; Nuria Izquierdo-Useros; Roger Paredes; Lourdes Mateu; Anna Chamorro; Marta Massanella; Jorge Carrillo; Bonaventura Clotet; Julià Blanco; Benjamin Pinsky; Manisha Desai; Julie Parsonnet; Upinder Singh

    doi:10.1101/2020.11.21.392753 Date: 2020-11-23 Source: bioRxiv

    Two proteases produced by the SARS-CoV-2 virus, Mpro PROTEIN and PLpro PROTEIN, are essential for viral replication and have become the focus of drug development programs for treatment of COVID-19 MESHD. We screened a highly focused library of compounds containing covalent warheads designed to target cysteine proteases to identify new lead scaffolds for both Mpro PROTEIN and PLpro PROTEIN proteases. These efforts identified a small number of hits for the Mpro PROTEIN protease and no viable hits for the PLpro PROTEIN protease. Of the Mpro PROTEIN 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 HGNC, 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 PROTEIN inhibitors are also potent inhibitors of host cell cysteine cathepsins. To determine if this is a general property of Mpro PROTEIN inhibitors, we evaluated several recently reported compounds and found that they are also effective inhibitors of purified human cathepsin L HGNC and B and showed similar loss in activity in cells expressing TMPRSS2 HGNC. Our results highlight the challenges of targeting Mpro PROTEIN and PLpro PROTEIN 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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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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