A Bioinorganic Approach to Coordinate Covalent Protease Inhibitors

PROJECT SUMMARY/ABSTRACT The primary objective of this proposal is to explore the ability of coordination complexes to serve as coordinate covalent inhibitors of cysteine proteases. We propose a hit-to-lead, systematic, proof-of-concept to syntheisize, characterize, and demonstrate the ability of Re(I) transition metal complexes to inhibit the SARS-CoV-2 main protease (3CLpro). To identify inhibitors of 3CLpro, this proposal will complete two specific aims. In Specific Aim 1, we will employ a library of bidentate ligands to generate ~150 distinct [Re(CO)3(L)(X)] complexes where 'L' represents different bidentate ligands and 'X' represents a leaving group (e.g., H2O). These complexes will be evaluated for their stability in buffer, reactivity with amino acids, and activity against 3CLpro. Specific Aim 1 will provide the initial hits to feed into Specific Aim 2. In Specific Aim 2, the most active hits identified in Specific Aim 1 will be further elaborated to establish a structure-activity relationship (SAR) and drive hit-to-lead development against 3CLpro. A typical design- synthesize-test iterative cycle will be used to develop the SAR and obtain increasingly better inhibitors. Upon completion of Specific Aim 2, we will complete the hit-to-lead effort, with the goal of obtaining at least one lead compound with an IC50 value of <50 nM against the SARS-CoV-2 3CLpro and good selectivity (IC50 >100 µM against non-target enzymes). This project will test the central hypothesis of whether metal-based compounds can provide a new class of covalent inhibitors against a relevant model target enzyme. Although not a drug discovery effort per se, our preliminary findings strongly suggest Re(I) complexes have the potential to generate potent and selective covalent inhibitors. In the long term, inhibitors derived from Re(I) complexes will demonstrate attractive features that are not readily achieved with conventional, organic inhibitors. For example, Re(I) compounds can be transformed into 'theranostics' simply by changing the choice of metal in (e.g., 99Tc). This proposal will provide a conceptual framework for exploring and exploiting the unique advantages afforded by metal-based therapeutics.