Preprint Article Version 1 This version is not peer-reviewed

Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity

Version 1 : Received: 5 May 2020 / Approved: 8 May 2020 / Online: 8 May 2020 (03:45:22 CEST)

How to cite: Mirza, M.U.; Ahmad, S.; Abdullah, I.; Froeyen, M. Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity. Preprints 2020, 2020050136 (doi: 10.20944/preprints202005.0136.v1). Mirza, M.U.; Ahmad, S.; Abdullah, I.; Froeyen, M. Identification of Novel Human USP2 Inhibitor: Might Involve in SARS-CoV-2 Papain-Like (PLpro) Protease Deubiquitination Activity. Preprints 2020, 2020050136 (doi: 10.20944/preprints202005.0136.v1).

Abstract

The ubiquitin-specific protease 2 (USP) belongs to the family of deubiquitinases and plays a critical role in tumors cells’ survival and therefore signifies an important therapeutic target. Previous studies have indicated promising efficacies of potent human USP2 inhibitors including, thiopurine analogues against SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb–palm–fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated structure-based virtual screening efforts. After a subsequent virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 value against Jurkat (9.67 µM) and MOTL-4 cells (11.8 µM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.

Subject Areas

deubiquitination; leukemia; ubiquitin-specific protease 2 (USP2); SARS-CoV-2 papain-like protease (PLpro); COVID-19

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.