Inhibitors of Deubiquitinating Enzymes Interfere with the SARS-CoV-2 Papain-like Protease and Block Virus Replication In Vitro

Große M, Setz C, Rauch P, Auth J, Morokutti-Kurz M, Temchura V, Schubert U (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Viruses MDPI

Book Volume: 14

Article Number: 1404

Journal Issue: 7

DOI: 10.3390/v14071404

Abstract

The ubiquitin proteasome system (UPS), particularly its deubiquitinating enzymes (DUBs), play a key role in the replication cycle of coronaviruses. The SARS-CoV-2 papain-like protease (Plpro) is known to process the viral polyproteins to form the replicase transcriptase complex and to counteract the host viral response. Recently, it was shown that this viral protease can also act as a deubiquitinating enzyme. In this study, we demonstrate that certain DUB-Inhibitors (DIs) interfere with SARS-CoV-2 replication. The DIs PR-619 and HBX41108 restrict SARS-CoV-2 in both Vero B4 and human Calu-3 lung cells where cells were infected with a Multiplicity of Infection (MOI) of 0.02. An in vitro protease assay using recombinant Plpro and Amido-4-methylcoumarin (AMC)-conjugated substrate revealed that PR-619 and HBX41108 are able to block the protease at concentrations where the interventions restricted virus replication. In contrast, DIs that do not inhibit Plpro had no influence on virus replication, which indicated that the protease might be at least one major target. Future vertical studies that would gain more insights into the mechanisms of how DUBs effect the replication of SARS-CoV-2 will further validate them as a potential therapeutic target.

Authors with CRIS profile

Maximilian Große Institute of Clinical and Molecular Virology Christian Setz Institute of Clinical and Molecular Virology Janina Auth Professur für Virologie Vladimir Temchura Institute of Clinical and Molecular Virology Ulrich Schubert Professur für Virologie

Involved external institutions

Marinomed Biotech AG

Austria (AT)

How to cite

APA:

Große, M., Setz, C., Rauch, P., Auth, J., Morokutti-Kurz, M., Temchura, V., & Schubert, U. (2022). Inhibitors of Deubiquitinating Enzymes Interfere with the SARS-CoV-2 Papain-like Protease and Block Virus Replication In Vitro. Viruses, 14(7). https://dx.doi.org/10.3390/v14071404

MLA:

Große, Maximilian, et al. "Inhibitors of Deubiquitinating Enzymes Interfere with the SARS-CoV-2 Papain-like Protease and Block Virus Replication In Vitro." Viruses 14.7 (2022).

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