Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2.

Affiliation

Weglarz-Tomczak E(1), Tomczak JM(2), Talma M(3), Burda-Grabowska M(3)(4), Giurg M(4), Brul S(5).
Author information:
(1)Molecular Biology and Microbial Food Safety Group, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands. [Email]
(2)Computational Intelligence Group, Department of Computer Science, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
(3)Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Science and Technology, Wrocław, Poland.
(4)Department of Organic and Medicinal Chemistry, Faculty of Chemistry, Wroclaw University of Science and Technology, Wrocław, Poland.
(5)Molecular Biology and Microbial Food Safety Group, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam, The Netherlands. [Email]

Abstract

An efficient treatment against a COVID-19 disease, caused by the novel coronavirus SARS-CoV-2 (CoV2), remains a challenge. The papain-like protease (PLpro) from the human coronavirus is a protease that plays a critical role in virus replication. Moreover, CoV2 uses this enzyme to modulate the host's immune system to its own benefit. Therefore, it represents a highly promising target for the development of antiviral drugs. We used Approximate Bayesian Computation tools, molecular modelling and enzyme activity studies to identify highly active inhibitors of the PLpro. We discovered organoselenium compounds, ebselen and its structural analogues, as a novel approach for inhibiting the activity of PLproCoV2. Furthermore, we identified, for the first time, inhibitors of PLproCoV2 showing potency in the nanomolar range. Moreover, we found a difference between PLpro from SARS and CoV2 that can be correlated with the diverse dynamics of their replication, and, putatively to disease progression.