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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

NSP5 (2)

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.

    Attacking COVID-19 MESHD Progression using Multi-Drug Therapy for Synergetic Target Engagement

    Authors: Mathew Coban; Juliet Morrison PhD; William D. Freeman MD; Evette Radisky PhD; Karine G. Le Roch PhD; Thomas R. Caulfield PhD

    id:2007.02557v1 Date: 2020-07-06 Source: arXiv

    COVID-19 MESHD is a devastating respiratory and inflammatory illness MESHD caused by a new coronavirus that is rapidly spreading throughout the human population. Over the past 6 months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19 MESHD, has already infected over 11.6 million (25% located in United States) and killed more than 540K people around the world. As we face one of the most challenging times in our recent history, there is an urgent need to identify drug candidates that can attack SARS-CoV-2 on multiple fronts. We have therefore initiated a computational dynamics drug pipeline using molecular modeling, structure simulation, docking and machine learning models to predict the inhibitory activity of several million compounds against two essential SARS-CoV-2 viral proteins and their host protein interactors; S/ Ace2 HGNC, Tmprss2 HGNC, Cathepsins L and K, and Mpro PROTEIN to prevent binding, membrane fusion and replication of the virus, respectively. All together we generated an ensemble of structural conformations that increase high quality docking outcomes to screen over >6 million compounds including all FDA-approved drugs, drugs under clinical trial (>3000) and an additional >30 million selected chemotypes from fragment libraries. Our results yielded an initial set of 350 high value compounds from both new and FDA-approved compounds that can now be tested experimentally in appropriate biological model systems. We anticipate that our results will initiate screening campaigns and accelerate the discovery of COVID-19 MESHD treatments.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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