2. Academic Validation
  3. Picomolar bivalent inhibitors of protein kinase CK2 active against β-coronavirus replication

Picomolar bivalent inhibitors of protein kinase CK2 active against β-coronavirus replication

  • Eur J Med Chem. 2025 May 29:296:117826. doi: 10.1016/j.ejmech.2025.117826.
Dylan Grenier 1,  Dennis Salomon Lopez Molina 2,  Muriel Gelin 3,  Angélique Mularoni 1,  Jean-François Guichou 3,  Jean-Guy Delcros 1,  Charlotte Martinasso 1,  Yinshan Yang 3,  Nazim Ahnou 2,  Jean-Michel Pawlotsky 4,  Abdelhakim Ahmed-Belkacem 2,  Isabelle Krimm 5
Affiliations

Affiliations

  • 1 University Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Institut Convergence Plascan, 69373 Lyon, France.
  • 2 Équipe "Virus, Hépatologie, Cancer", INSERM U955, IMRB, Université Paris-Est, Créteil, France.
  • 3 Centre de Biologie Structurale (CBS), University of Montpellier, CNRS UMR 5048, INSERM U1054, Montpellier, France.
  • 4 Équipe "Virus, Hépatologie, Cancer", INSERM U955, IMRB, Université Paris-Est, Créteil, France; Department of Virology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France.
  • 5 University Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Institut Convergence Plascan, 69373 Lyon, France. Electronic address: isabelle.krimm@univ-lyon1.fr.
PMID: 40482595 DOI: 10.1016/j.ejmech.2025.117826
Abstract

The protein Casein Kinase 2 (CK2) has been shown to be upregulated in SARS-CoV-2 infections. However, few inhibitors have been tested for Antiviral activity against coronaviruses. In this study, highly potent and selective bivalent inhibitors targeting the protein kinase CK2 were developed. The chemical structure of the well-known inhibitor CX-4945 was used as an anchor for the ATP-binding site and was linked by polar and aliphatic linkers to chemical structures that bind the cryptic αD pocket of CK2. The bivalent inhibitor Biv5, which demonstrated a sub-nanomolar kinase inhibition, showed potent Antiviral activity against SARS-CoV-2 in HEK-ACE2-TMPRSS2 and Vero cells. In addition, Biv5 significantly reduced viral replication over time in an ex vivo model of primary human nasal epithelial cells. The selectivity of Biv5 was tested against 16 kinases targeted by CX-4945, confirming that targeting the αD pocket confers high selectivity for CK2 to such inhibitors.

Keywords

Bivalent inhibitor; Casein kinase 2; Coronavirus; Cryptic pocket; Linker.

Figures
Products