The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted an urgent need for development of new antiviral drugs. The main protease (Mpro) of SARS-CoV-2 plays an important role in viral replication and has become as an attractive drug target for virus inhibition. The active site of SARS-CoV-2 Mpro contains Cys145 and His41 which allows to use structural subunits (or “warheads”) for covalent binding to the thiol of a cysteine residue in the active site of cysteine proteases.
In our design of inhibitors considerably less chemically reactive and non-toxic lactams and their structural analogues as “warheads” for covalent inhibition of SARS-CoV-2 proteases Mpro were chosen. β- And ɣ-lactam subunit serves as the warhead for the covalent modification of cysteine proteases with the mechanism of action involving the cleavage of β-lactam ring by cysteine residue in the active site of the enzyme.
For chosen β- and ɣ-lactams IC50 values for Mpro inhibition were determined using fluorescence resonance energy transfer (FRET) assay. For inhibitory activity improvement (1H-indole-2-carbonyl)-L-phenylalanine moiety was introduced.
This work was supported by the project 188.8.131.52/VIAA/4/20/754 “Development of lactam-based inhibitors of SARS-CoV-2 Mpro and other viral proteases”.
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