Infections of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have triggered a global pandemic with millions of deaths worldwide. Herein, the synthesis of functionalized Re(i) tricarbonyl complexes as inhibitors of the SARS-CoV-2 main protease, also referred to as the 3-chymotrypsin-like protease (3CLpro), is presented. The metal complexes were found to inhibit the activity of the enzyme with IC50 values in the low micromolar range. Mass spectrometry revealed that the metal complexes formed a coordinate covalent bond with the enzyme. Chiral separation of the enantiomers of the lead compound showed that one enantiomer was significantly more active than the other, consistent with specific binding and much like that observed for conventional organic small molecule inhibitors and druglike compounds. Evaluation of the lead compound against SARS-CoV-2 in a cell-based infection assay confirmed enantiospecific inhibition against the virus. This study represents a significant advancement in the use of metal complexes as coordinate covalent inhibitors of enzymes, as well as a novel starting point for the development of novel SARS-CoV-2 inhibitors.
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