Computational design and optimization of small molecule and protein inhibitors for the use against variants of SARS-CoV-2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is still causing major global health and economic implications. While vaccines continue to advance in clinical trials and three vaccines have been approved by the FDA for emergency use authorization or full approval in the United States, there is still an unmet need to deliver therapeutic options to those infected, especially in hospitalized patients. SARS-CoV-2 variants of concern continue to arise, decreasing vaccine efficacy, and decreasing efficacy of emergency use antibody therapies. Our goal is to computationally design and experimentally test a number of SARS-CoV-2 protein-based and small molecule therapies that are resistant to current and developing variants of concern and that also display pancoronavirus activity to help combat future coronavirus strains. We will de novo design of SARS-CoV-2 Mpro inhibitors, soluble ACE2 (sACE2) decoy receptor against the receptor-binding-domain (RBD) of SARS-CoV-2 and peptide inhibitors that will prevent the viral fusion to the cell membrane. The administration of these three therapies as a cocktail may act to potently neutralize SARS-CoV-2 virus in infected patients, be resistant to current and developing variants, and can potentially be used as a pancoronvirus therapy for the emergence of future coronavirus strains.