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Ahmed-Belkacem A, Colliandre L, Ahnou N, et al. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities. Nat Commun. 2016;7:12777doi: 10.1038/ncomms12777.
Ahmed-Belkacem, A., Colliandre, L., Ahnou, N., Nevers, Q., Gelin, M., Bessin, Y., Brillet, R., Cala, O., Douguet, D., Bourguet, W., Krimm, I., Pawlotsky, J. M., & Guichou, J. F. (2016). Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities. Nature communications, 712777. https://doi.org/10.1038/ncomms12777
Ahmed-Belkacem, Abdelhakim, et al. "Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities." Nature communications vol. 7 (2016): 12777. doi: https://doi.org/10.1038/ncomms12777
Ahmed-Belkacem A, Colliandre L, Ahnou N, Nevers Q, Gelin M, Bessin Y, Brillet R, Cala O, Douguet D, Bourguet W, Krimm I, Pawlotsky JM, Guichou JF. 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. PMID: 27652979; PMCID: PMC5036131.
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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.

Nature communications

Abdelhakim Ahmed-Belkacem, Lionel Colliandre, Nazim Ahnou, Quentin Nevers, Muriel Gelin, Yannick Bessin, Rozenn Brillet, Olivier Cala, Dominique Douguet, William Bourguet, Isabelle Krimm, Jean-Michel Pawlotsky, Jean-François Guichou

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 PMCID: PMC5036131 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.

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

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