Abstract
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 (Mpro), 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 Mpro 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.
Highlights
The recent outbreak of COVID-19 pandemic, caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), has raised serious global concern for public health
In the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays
The rational design of shorter analogues was based on molecular dynamics investigation, integrated by MM-GBSA predictions, of AT1001 bound to main protease (Mpro) showing that the N- and C-terminal residues (G1, Q6, P7 and G8) fluctuated largely than the remaining amino acids [16]
Summary
The recent outbreak of COVID-19 pandemic, caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), has raised serious global concern for public health. In all coronaviruses the replication phase is initiated by production of the replicase proteins with the translation of ORF1a and ORF1ab via a –1 ribosomal frame-shifting mechanism [6] This mechanism produces two large viral polyproteins, pp1a and pp1ab (~450 and ~790 kDa, respectively), which are cleaved into 16 non-structural proteins (Nsp1–Nsp16), required for correct viral replication and transcription [7,8]. Mpro digests the polyprotein 1ab at multiple cleavage sites by hydrolysis of the Gln-Ser peptide bond mainly in the Leu-Gln-Ser-Ala-Gly recognition sequence [10], leading to the formation of non-structural proteins (NSPs) This cleavage site in the substrate is distinct from the peptide sequence recognized by human homologs, decreasing the possibility to interfere with off-targets in the host
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