2. Academic Validation
  3. Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors

Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors

  • Eur J Med Chem. 2022 Dec 15;247:115021. doi: 10.1016/j.ejmech.2022.115021.
Santo Previti 1,  Roberta Ettari 2,  Elsa Calcaterra 2,  Salvatore Di Maro 3,  Stefan J Hammerschmidt 4,  Christin Müller 5,  John Ziebuhr 5,  Tanja Schirmeister 4,  Sandro Cosconati 6,  Maria Zappalà 2
Affiliations

Affiliations

  • 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d'Alcontres 31, 98166, Messina, Italy. Electronic address: [email protected].
  • 2 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d'Alcontres 31, 98166, Messina, Italy.
  • 3 DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy.
  • 4 Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, 55128, Mainz, Germany.
  • 5 Institute of Medical Virology Justus Liebig University, Gießen Schubertstr. 81, 35392, Gießen, Germany.
  • 6 DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy. Electronic address: [email protected].
PMID: 36549112 DOI: 10.1016/j.ejmech.2022.115021
Abstract

Despite several major achievements in the development of vaccines and antivirals, the fight against SARS-CoV-2 and the health problems accompanying COVID-19 are still ongoing. SARS-CoV-2 main protease (Mpro), an essential viral cysteine protease, is a crucial target for the development of Antiviral agents. A virtual screening analysis of in-house cysteine Protease Inhibitors against SARS-CoV-2 Mpro allowed us to identify two hits (i.e., 1 and 2) bearing a methyl vinyl ketone warhead. Starting from these compounds, we herein report the development of Michael acceptors targeting SARS-CoV-2 Mpro, which differ from each other for the warhead and for the Amino acids at the P2 site. The most promising vinyl methyl ketone-containing analogs showed sub-micromolar activity against the viral protease. SPR38, SPR39, and SPR41 were fully characterized, and additional inhibitory properties towards hCatL, which plays a key role in the virus entry into host cells, were observed. SPR39 and SPR41 exhibited single-digit micromolar EC50 values in a SARS-CoV-2 Infection model in Cell Culture.

Keywords

Antiviral activity; COVID-19; Michael acceptors; Peptide-based inhibitors; SARS-CoV-2 M(pro) inhibition.

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