ReI Tricarbonyl Complexes as Coordinate Covalent Inhibitors for the SARS-CoV-2 Main Cysteine Protease

Since its outbreak, the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has impacted the quality of life and cost hundreds-of-thousands of lives worldwide. Based on its global spread and mortality, there is an urgent need for novel treatments which can combat this disease. To date, the 3-chymotrypsin-like protease (3CL(pro)), which is also known as the main protease, is considered among the most important pharmacological targets. The vast majority of investigated 3CL(pro) inhibitors are organic, non-covalent binders. Herein, the use of inorganic, coordinate covalent binders is proposed that can attenuate the activity of the protease. Re-I tricarbonyl complexes were identified that demonstrate coordinate covalent enzymatic inhibition of 3CL(pro). Preliminary studies indicate the selective inhibition of 3CL(pro) over several human proteases. This study presents the first example of metal complexes as inhibitors for the 3CL(pro) cysteine protease.