Bespoke transition state analog inhibitors of SARS-CoV-2 3CL and PL proteases [Added supplements: COVID-19 Variant Supplement, COVID-19 Variant Network]

SARS-CoV-2 is devastating global health and economies. Rapid development of antiviral drugs is critical to treat disease in the short term and beyond. Logical antiviral targets are the proteases 3CLpro and PLpro, responsible for processing of long chains of linked viral proteins produced during viral reproduction. 3CLpro and PLpro are enzymes that harness pac-man like activity to clip the chains into individual proteins. This cleavage process is essential for formation of new disease causing virus. If you block the pac-man activity, you stop the virus in its tracks. Similar types of viruses have been targeted very successfully by drug development in other important global viruses such as HIV. Understanding inhibitor binding to 3CLpro and PLpro at the atomic level is central to antiviral drug development. We are harnessing our significant expertise in xray crystallography and single particle cryoEM, biophsyical techniques that allow us to determine atomic pictures of these proteases in the presence of bound drug. Leveraging our prior work on similar enzymes with international leading antimicrobial pharmaceutical teams we have identified tight binding drug leads that take advantage of the unique features of these enzymes. We aim to optimize these compounds through structure-guided techniques (using our atomic blueprints so to speak) and the antiviral drug discovery pipeline of our industry partner.