Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential Anti SARS-CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus Enzyme, called 3CLpro or main protease (M^pro), is essential for viral replication, making it a most promising target for Antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds M^pro catalytic domain. Thus, in the present study we tried to investigate the Antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of Antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.

FRET; MM-GBSA; SARS-CoV-2; antiviral; drug repurposing; molecular docking; molecular dynamics; peptide.