The lives of humans worldwide have been significantly impacted by COVID-19 which resulted in a global pandemic due to coronavirus 2 (SARS-CoV-2). The ongoing persistence of the virus, vaccine hesitancy and breakthrough cases urges scientist and medical authorities to come together and develop drug-based treatment alternatives for COVID-19. Two proteases, main protease (Mpro) and papain-like protease (PLpro), have been identified as ideal drug targets due to their role in cleaving vital virus polypeptides. Inspired by a potent feline coronavirus drug (GC376), novel peptide aldehydes have been recently developed that bind with nanomolar concentrations to Mpro. The synthesis of these aldehydes involves elaborate cyclization and oxidation reactions connected with sophisticated column purification and yield limitations. In this study optimized peptide aldehyde synthesis incorporating amino acid surrogates that facilitate target purification and increase yield are presented. <i>In vivo </i>effectivity of respective target aldehydes using a FRET based assay indicates nanomolar Mpro inhibition. If successful in cell-based assays and further engineered, these aldehydes reflect promising lead compounds in developing a drug-based treatment alternative for COVID-19.

Engineered peptide aldehydes as potent antiviral drugs against SARS-CoV-2

ACS Spring 2022

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