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Nat Commun. 2016 Sep 22;7:12777. doi: 10.1038/ncomms12777.

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

Author information

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.

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.

Conflict of interest statement

Inserm Transfert is the owner of patent EP 09306294.1 covering the family of cyclophilin inhibitors described, for which A.A.-B., L.C., J.-M.P. and J.-F.G. are inventors. All other authors declare no competing financial interests.

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