4-(3-Phenylsulfonylindol-2-yl)-1-(pyridin-2-yl)piperazinyl-methanones as Potent Inhibitors of both SARS-CoV-2 and HCoV-OC43 Viruses

  • ACS Infect Dis. 2024 Aug 3. doi: 10.1021/acsinfecdis.4c00108.
Michela Puxeddu  1 ,  Manuela Donalisio  2 ,  Joachim Jakob Bugert  3 ,  Angela Corona  4 ,  Paolo Cocomazzi  5 ,  Mario Milani  5 ,  Friederike Hucke  3 ,  Irene Arduino  2 ,  Francesca Esposito  4 ,  Paolo Moretti  6 ,  Maria Grazia Ortore  6 ,  Marianna Nalli  1 ,  Simone Manetto  1 ,  Giulia Mazzoccanti  1 ,  Chiara Bigogno  7 ,  Giulio Dondio  7 ,  Pietro Sciò  1 ,  Antonio Coluccia  1 ,  Matteo Fracella  8 ,  Guido Antonelli  8 ,  David Lembo  2 ,  Enzo Tramontano  4 ,  Romano Silvestri  1 ,  Eloise Mastrangelo  5 ,  Giuseppe La Regina  1
Affiliations
  • 1. Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, I-00185 Rome, Italy.
  • 2. Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, I-10043 Orbassano, Turin, Italy.
  • 3. Institut für Mikrobiologie der Bundeswehr, Neuherbergstrasse 11, D-80937 München, Germany.
  • 4. Department of Life and Environmental Sciences, University of Cagliari, S.P. 8 Monserrato, Sestu Km 0.700, I-09042 Monserrato, Italy.
  • 5. Biophysics Institute, CNR-IBF, Via Corti 12, I-20133 Milan, Italy.
  • 6. DISVA, Department of Life Sciences and Environment, Università Politecnica delle Marche, Via Brecce Bianche, I-60131 Ancona, Italy.
  • 7. Aphad SrL, Via della Resistenza 65, 20090 Buccinasco, Italy.
  • 8. Laboratory of Virology, Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy.
PMID: 39096289 DOI: 10.1021/acsinfecdis.4c00108
Abstract

SARS-CoV-2 and HCoV-OC43 belong to the same β genus of the Coronaviridae family. SARS-CoV-2 was responsible for the recent COVID-19 pandemic, and HCoV-OC43 is the etiological agent of mild upper respiratory tract infections. SARS-COV-2 and HCoV-OC43 co-infections were found in children with respiratory symptoms during the COVID-19 pandemic. The two β-coronaviruses share a high degree of homology between the 3CLpro active sites, so much so that the safer HCoV-OC43 has been suggested as a tool for the identification of new anti-SARS-COV-2 agents. Compounds 5 and 24 inhibited effectively both Wuhan and British SARS-CoV-2 patient isolates in Vero E6 cells and the HCoV-OC43 in MRC-5 cells at low micromolar concentrations. The inhibition was apparently exerted via targeting the 3CLpro active sites of both viruses. Compounds 5 and 24 at 100 μM inhibited the SARS-CoV-2 3CLpro activity of 61.78 and 67.30%, respectively. These findings highlight 5 and 24 as lead compounds of a novel class of Antiviral agents with the potential to treat SARS-COV-2 and HCoV-OC43 infections.

Keywords
3CL protease; HCoV-OC43; SARS-CoV-2; antiviral drugs; synthesis.
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