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Identification of a dual acting SARS-CoV-2 proteases inhibitor through in silico design and step-by-step biological characterization.
Di Sarno, Veronica; Lauro, Gianluigi; Musella, Simona; Ciaglia, Tania; Vestuto, Vincenzo; Sala, Marina; Scala, Maria Carmina; Smaldone, Gerardina; Di Matteo, Francesca; Novi, Sara; Tecce, Mario Felice; Moltedo, Ornella; Bifulco, Giuseppe; Campiglia, Pietro; Gomez-Monterrey, Isabel M; Snoeck, Robert; Andrei, Graciela; Ostacolo, Carmine; Bertamino, Alessia.
Afiliación
  • Di Sarno V; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Lauro G; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Musella S; European Biomedical Research Institute (EBRIS), Via S. De Renzi 50, 84125, Salerno, Italy.
  • Ciaglia T; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Vestuto V; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Sala M; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Scala MC; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Smaldone G; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Di Matteo F; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Novi S; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Tecce MF; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Moltedo O; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Bifulco G; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy.
  • Campiglia P; 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.
  • Gomez-Monterrey IM; Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131, Naples, Italy.
  • Snoeck R; Rega Institute for Medical Research, Department of Microbiology, Immunology, and Transplantation, KU Leuven, BE-3000, Leuven, Belgium.
  • Andrei G; Rega Institute for Medical Research, Department of Microbiology, Immunology, and Transplantation, KU Leuven, BE-3000, Leuven, Belgium.
  • Ostacolo C; Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131, Naples, Italy. Electronic address: ostacolo@unina.it.
  • Bertamino A; Department of Pharmacy, University of Salerno, Via G. Paolo II 132, 84084, Fisciano, Salerno, Italy. Electronic address: abertamino@unisa.it.
Eur J Med Chem ; 226: 113863, 2021 Dec 15.
Article en En | MEDLINE | ID: mdl-34571172
COVID-19 pandemic, starting from the latest 2019, and caused by SARS-CoV-2 pathogen, led to the hardest health-socio-economic disaster in the last century. Despite the tremendous scientific efforts, mainly focused on the development of vaccines, identification of potent and efficient anti-SARS-CoV-2 therapeutics still represents an unmet need. Remdesivir, an anti-Ebola drug selected from a repurposing campaign, is the only drug approved, so far, for the treatment of the infection. Nevertheless, WHO in later 2020 has recommended against its use in COVID-19. In the present paper, we describe a step-by-step in silico design of a small library of compounds as main protease (Mpro) inhibitors. All the molecules were screened by an enzymatic assay on Mpro and, then, cellular activity was evaluated using Vero cells viral infection model. The cellular screening disclosed compounds 29 and 34 as in-vitro SARS-CoV-2 replication inhibitors at non-toxic concentrations (0.32 < EC50 < 5.98 µM). To rationalize these results, additional in-vitro assays were performed, focusing on papain like protease (PLpro) and spike protein (SP) as potential targets for the synthesized molecules. This pharmacological workflow allowed the identification of compound 29, as a dual acting SARS-CoV-2 proteases inhibitor featuring micromolar inhibitory potency versus Mpro (IC50 = 1.72 µM) and submicromolar potency versus PLpro (IC50 = 0.67 µM), and of compound 34 as a selective SP inhibitor (IC50 = 3.26 µM).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Inhibidores de Proteasas / Diseño de Fármacos / SARS-CoV-2 Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2021 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Francia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antivirales / Inhibidores de Proteasas / Diseño de Fármacos / SARS-CoV-2 Tipo de estudio: Diagnostic_studies Límite: Animals Idioma: En Revista: Eur J Med Chem Año: 2021 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Francia