2. Academic Validation
  3. Easy access to α-ketoamides as SARS-CoV-2 and MERS Mpro inhibitors via the PADAM oxidation route

Easy access to α-ketoamides as SARS-CoV-2 and MERS Mpro inhibitors via the PADAM oxidation route

  • Eur J Med Chem. 2022 Dec 15;244:114853. doi: 10.1016/j.ejmech.2022.114853.
Sveva Pelliccia 1,  Carmen Cerchia 2,  Francesca Esposito 3,  Rolando Cannalire 2,  Angela Corona 3,  Elisa Costanzi 4,  Maria Kuzikov 5,  Philip Gribbon 6,  Andrea Zaliani 6,  Margherita Brindisi 2,  Paola Storici 4,  Enzo Tramontano 3,  Vincenzo Summa 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy. Electronic address: sveva.pelliccia@unina.it.
  • 2 Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy.
  • 3 Dipartimento di Scienze della Vita e dell'Ambiente, Cittadella Universitaria di Monserrato, Cagliari, Monserrato, SS-554, Italy.
  • 4 Protein Facility, Elettra - Sincrotrone Trieste S.C.p.A., SS 14 - km 163, 5 in AREA Science Park, Trieste, Basovizza, 34149, Italy.
  • 5 Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, Hamburg, 22525, Germany; Department of Life Sciences and Chemistry, Jacobs University Bremen, 28759, Bremen, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
  • 6 Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, Hamburg, 22525, Germany; Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany.
  • 7 Department of Pharmacy, University of Naples Federico II, via D. Montesano 49, 80131, Naples, Italy. Electronic address: vincenzo.summa@unina.it.
PMID: 36332546 DOI: 10.1016/j.ejmech.2022.114853
Abstract

SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient Antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral Enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel Antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed μM to nM activities in enzymatic and in the Antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.

Keywords

Main protease inhibitors; Multicomponent reactions; PADAM-Oxidation; SARS-CoV-2; α-ketoamides.

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