2. Academic Validation
  3. Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2

Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2

  • Eur J Med Chem. 2022 Dec 15;244:114857. doi: 10.1016/j.ejmech.2022.114857.
Simone Di Micco 1,  Rahila Rahimova 2,  Marina Sala 3,  Maria C Scala 3,  Giovanni Vivenzio 3,  Simona Musella 4,  Graciela Andrei 5,  Kim Remans 6,  Léa Mammri 2,  Robert Snoeck 5,  Giuseppe Bifulco 3,  Francesca Di Matteo 3,  Vincenzo Vestuto 3,  Pietro Campiglia 4,  José A Márquez 7,  Alessio Fasano 8
Affiliations

Affiliations

  • 1 European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore de Renzi 50, 84125, Salerno, Italy. Electronic address: [email protected].
  • 2 European Molecular Biology Laboratory, EMBL, 71 Avenue des Martyrs, CS 90181, Grenoble Cedex 9, 38042, France.
  • 3 Dipartimento di Farmacia, Università Degli Studi di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • 4 European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore de Renzi 50, 84125, Salerno, Italy; Dipartimento di Farmacia, Università Degli Studi di Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • 5 Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000, Leuven, Belgium.
  • 6 European Molecular Biology Laboratory, EMBL, Meyerhofstraße 1, 69117, Heidelberg, Germany.
  • 7 European Molecular Biology Laboratory, EMBL, 71 Avenue des Martyrs, CS 90181, Grenoble Cedex 9, 38042, France; ALPX S.A.S. 71, Avenue des Martyrs, France.
  • 8 European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore de Renzi 50, 84125, Salerno, Italy; Mucosal Immunology and Biology Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, MA, 02114, USA.
PMID: 36332548 DOI: 10.1016/j.ejmech.2022.114857
Abstract

Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 Mpro. By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with Mpro C145. In vitro Antiviral tests indicate the improvement of biological activity of 4 respect to AT1001. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evaluation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration.

Keywords

Antiviral; Covalent inhibitors; Molecular modeling; SARS-CoV-2; X-ray crystallography.

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