Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections

Abstract

Ebselen is an organoselenium compound exhibiting hydroperoxide- and peroxynitrite-reducing activity, acting as a glutathione peroxidase and peroxiredoxin enzyme mimetic. Ebselen reacts with a multitude of protein thiols, forming a selenosulfide bond, which results in pleiotropic effects of antiviral, antibacterial and anti-inflammatory nature. The main protease (M^pro) of the corona virus SARS-CoV-2 is a potential drug target, and a screen with over 10,000 compounds identified ebselen as a particularly promising inhibitor of M^pro (Jin, Z. et al. (2020) Nature 582, 289-293). We discuss here the reaction of ebselen with cysteine proteases, the role of ebselen in infections with viruses and with other microorganisms. We also discuss effects of ebselen in lung inflammation. In further research on the inhibition of M^pro in SARS-CoV-2, ebselen can serve as a promising lead compound, if the inhibitory effect is confirmed in intact cells in vivo. Independently of this action, potential beneficial effects of ebselen in COVID-19 are ascribed to a number of targets critical to pathogenesis, such as attenuation of inflammatory oxidants and cytokines.

Keywords: Cysteine protease; Lung inflammation; Organoselenium compounds; SARS-CoV-2.

Graphical abstract

Fig. 1

Depiction of the potential role of inhibitors of the main protease M^proin the SARS-CoV-2 life cycle in the cell. Inhibitors of protease M^pro prevent the replication of SARS-CoV-2. After entering into the host cell, SARS-CoV-2 releases its genomic RNA. The process of translation yields polyproteins pp1a and pp1ab, which are cleaved to form the main protease M^pro and nonstructural proteins (nsps). M^pro is involved in the production of nsps. Nsps is essential for assembly during viral replication. Modified from Mengist et al. [92]. Creative Commons License.

Fig. 2

In silico analysis of ebselen bound to the main protease M^proof Sars-Cov-2 (PDB code:6Y2E). The selenium atom of the open structure of ebselen (green) establishes a covalent interaction with the M^pro catalytic cysteine (Cys-145). His-41 forms a p-stacking interaction with the aromatic ring of ebselen, and a polar interaction with its carbonyl group. In silico analysis was performed using MOE and ACEMD softwares. Kindly provided by Prof. G. Cozza, Padova.

Fig. 3

Potential effects of ebselen on viral activity, pulmonary inflammatory responses and circulatory disturbances during COVID-19 infection. Ebselen can target virus sites directly, notably M^pro. It also addresses key sites in the host, attenuating the overproduction of ROS and cytokines and neutrophil infiltration, thereby counteracting pulmonary and vascular inflammation.