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  3. Peptidomimetics as potent dual SARS-CoV-2 cathepsin-L and main protease inhibitors: In silico design, synthesis and pharmacological characterization

Peptidomimetics as potent dual SARS-CoV-2 cathepsin-L and main protease inhibitors: In silico design, synthesis and pharmacological characterization

  • Eur J Med Chem. 2024 Feb 15:266:116128. doi: 10.1016/j.ejmech.2024.116128.
Tania Ciaglia 1,  Vincenzo Vestuto 1,  Veronica Di Sarno 1,  Simona Musella 1,  Gerardina Smaldone 1,  Francesca Di Matteo 1,  Valeria Napolitano 1,  Maria Rosaria Miranda 1,  Giacomo Pepe 1,  Manuela Giovanna Basilicata 1,  Sara Novi 1,  Ilaria Capolupo 1,  Giuseppe Bifulco 1,  Pietro Campiglia 2,  Isabel Gomez-Monterrey 3,  Robert Snoeck 4,  Graciela Andrei 4,  Michele Manfra 5,  Carmine Ostacolo 1,  Gianluigi Lauro 6,  Alessia Bertamino 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • 2 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy; European Biomedical Research Institute (EBRIS), Via S. De Renzi 50, 84125, Salerno, Italy.
  • 3 Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131, Naples, Italy.
  • 4 Rega Institute for Medical Research, Department of Microbiology, Immunology, and Transplantation, KU Leuven, BE-3000, Leuven, Belgium.
  • 5 Department of Science, University of Basilicata, Via Dell'Ateneo Lucano 10, 85100, Potenza, Italy.
  • 6 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy. Electronic address: glauro@unisa.it.
  • 7 Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy. Electronic address: abertamino@unisa.it.
PMID: 38232463 DOI: 10.1016/j.ejmech.2024.116128
Abstract

In this paper we present the design, synthesis, and biological evaluation of a new series of peptidomimetics acting as potent anti-SARS-CoV-2 agents. Starting from our previously described Main Protease (MPro) and Papain Like Protease (PLPro) dual inhibitor, CV11, here we disclose its high inhibitory activity against Cathepsin L (CTSL) (IC50 = 19.80 ± 4.44 nM), an emerging target in SARS-CoV-2 Infection machinery. An in silico design, inspired by the structure of CV11, led to the development of a library of peptidomimetics showing interesting activities against CTSL and Mpro, allowing us to trace the chemical requirements for the binding to both Enzymes. The screening in Vero cells infected with 5 different SARS-CoV-2 variants of concerns, highlighted sub-micromolar activities for most of the synthesized compounds (13, 15, 16, 17 and 31) in agreement with the enzymatic inhibition assays results. The compounds showed lack of activity against several different RNA viruses except for the 229E and OC43 human coronavirus strains, also characterized by a cathepsin-L dependent release into the host cells. The most promising derivatives were also evaluated for their chemical and metabolic in-vitro stability, with derivatives 15 and 17 showing a suitable profile for further preclinical characterization.

Keywords

Antiviral drugs; In silico design; In-cell assays; Pepetidomimetcs; SARS-CoV-2 cathepsin-L and main protease inhibition.

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