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

Int J Mol Sci. 2021 Aug 30;22(17):9427. doi: 10.3390/ijms22179427.

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.

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

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Binding Sites
  • COVID-19 / virology
  • COVID-19 Drug Treatment
  • Catalytic Domain
  • Cell Line
  • Cytomegalovirus / drug effects
  • Drug Repositioning
  • Herpesvirus 3, Human / drug effects
  • Humans
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation
  • Oligopeptides / chemistry*
  • Peptides / chemical synthesis
  • Peptides / metabolism*
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / metabolism
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / metabolism

Substances

  • Antiviral Agents
  • Oligopeptides
  • Peptides
  • Viral Matrix Proteins
  • membrane protein, SARS-CoV-2
  • larazotide acetate