Session: Posters:

Since its outbreak, the severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2) has spread across the world. On 11^th March 2020, the World Health Organization officially declared this pulmonary disease as a global pandemic. To date, more than 90 million cases have been reported with more than 1.9 million confirmed deaths, creating an urgent need for the development of novel therapeutics.

To combat this disease, various different targets and drug strategies have been pursued. Among these, the 3-chymotrypsin-like protease (3CL^pro), which is also known as the main protease, is considered one of the most important viral targets for SARS-CoV-2. This protease is responsible for the processing of viral polyproteins that mediate functions required for viral replication and transcription and are crucial for viral maturation and infectivity. An inhibitor of 3CL^pro would significantly disrupt the viral life cycle, presenting an important opportunity for therapeutic intervention. To date, the vast majority of investigated 3CL^pro inhibitors are organic, non-covalent binders.

Herein, the application of inorganic, coordinate covalent inhibitors is proposed. Using computational docking experiments, Re(I) tricarbonyl complexes were identified as potential binders. Capitalizing on this, a series of metal complexes with chloride and water as capping ligands and functionalized 2,2’-bipyridine ligands were prepared. Using an in vitro 3CL^pro assay, several compounds were found with IC₅₀ values below 20 μM. Preliminary studies show high selectivity of these Re(I) compounds to inhibit 3CL^pro over other human proteases. Using a protein mass spectrometric analysis, the coordinate covalent binding of the metal complex towards 3CL^pro was verified. These results suggest that Re(I) tricarbonyl complexes can serve as a scaffold for the development of potent, selective SARS-CoV-2 inhibitors.

Docking pose of the [Re(2,2’-bipyridine)(CO)<sub>3</sub>]<sup>+</sup> fragment bound to Cys145 of 3CL<sup>pro</sup> with an electrostatic surface.

Docking pose of the [Re(2,2’-bipyridine)(CO)₃]⁺ fragment bound to Cys145 of 3CL^pro with an electrostatic surface.

Seth Cohen

U.C. San Diego

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