Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities

  • Nat Commun. 2016 Sep 22;7:12777. doi: 10.1038/ncomms12777.
Abdelhakim Ahmed-Belkacem  1 ,  Lionel Colliandre  2  3 ,  Nazim Ahnou  1 ,  Quentin Nevers  1 ,  Muriel Gelin  2  3 ,  Yannick Bessin  2  3 ,  Rozenn Brillet  1 ,  Olivier Cala  4 ,  Dominique Douguet  2  3 ,  William Bourguet  2  3 ,  Isabelle Krimm  4 ,  Jean-Michel Pawlotsky  1  5 ,  Jean-François Guichou  2  3
Affiliations
  • 1. INSERM U955 'Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers', Hôpital Henri Mondor, Université Paris-Est, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
  • 2. CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
  • 3. INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
  • 4. Institut des Sciences Analytiques, CNRS UMR5280, Université Lyon 1, École Nationale Supérieure de Lyon, 5 rue de la Doua, 69100 Villeurbanne, France.
  • 5. National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
PMID: 27652979 DOI: 10.1038/ncomms12777
Abstract

Cyclophilins are peptidyl-prolyl cis/trans isomerases (PPIase) that catalyse the interconversion of the peptide bond at proline residues. Several cyclophilins play a pivotal role in the life cycle of a number of viruses. The existing Cyclophilin inhibitors, all derived from cyclosporine A or sanglifehrin A, have disadvantages, including their size, potential for side effects unrelated to Cyclophilin inhibition and drug-drug interactions, unclear Antiviral spectrum and manufacturing issues. Here we use a fragment-based drug discovery approach using nucleic magnetic resonance, X-ray crystallography and structure-based compound optimization to generate a new family of non-peptidic, small-molecule Cyclophilin inhibitors with potent in vitro PPIase inhibitory activity and Antiviral activity against hepatitis C virus, human immunodeficiency virus and coronaviruses. This family of compounds has the potential for broad-spectrum, high-barrier-to-resistance treatment of viral infections.

Products