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

An efficient treatment against a COVID-19 disease, caused by the novel coronavirus SARS-CoV-2 (CoV2), remains a challenge. The papain-like protease (PL(pro)) 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 PL(pro). We discovered organoselenium compounds, ebselen and its structural analogues, as a novel approach for inhibiting the activity of PL(pro)CoV2. Furthermore, we identified, for the first time, inhibitors of PL(pro)CoV2 showing potency in the nanomolar range. Moreover, we found a difference between PL(pro) from SARS and CoV2 that can be correlated with the diverse dynamics of their replication, and, putatively to disease progression.