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. 2021 Aug 30;22(17):9427.
doi: 10.3390/ijms22179427.

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

Simone Di Micco  1 , Simona Musella  1 , Marina Sala  2 , Maria C Scala  2 , Graciela Andrei  3 , Robert Snoeck  3 , Giuseppe Bifulco  2 , Pietro Campiglia  2 , Alessio Fasano  1   4
Affiliations

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

Simone Di Micco et al. Int J Mol Sci. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
3D model of the interaction between N3 and Mpro. The protein is represented by gold molecular surface and green tubes (atom color code: C, as tubes; polar H, sky blue; N, dark blue; O, red; S, yellow). N3 is depicted by magenta tubes (atom color code as for protein). The protein sub-pockets are indicated by red labels. The black dashed lines indicate ligand-protein H-bonds.
Figure 2
Figure 2
2D panel representing interactions formed by fragments 2 (a), 3 (b), 4 (c), 5 (d) and 6 (e) with Mpro. In each panel (a–e) the molecular structure of 2–6 is depicted in black, while the protein amino acids are indicated with three letter code, encircled with colored lines (negatively charged amino acids, red; positively charged amino acids, dark blue; polar amino acids, light blue; hydrophobic amino acids, green circles). The purple arrows indicate H-bonds. The arrows are directed from donor to acceptor of H-bond.
Scheme 1
Scheme 1
On resin N-methylation.
See this image and copyright information in PMC

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