title: Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities.
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.
authors.affiliation: 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.
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Ahmed-Belkacem
authors.affiliation: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.|INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Colliandre
authors.affiliation: 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.
authors.forename: Nazim
authors.initials: N
authors.lastname: Ahnou
authors.affiliation: 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.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Nevers
authors.affiliation: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.|INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Gelin
authors.affiliation: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.|INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bessin
authors.affiliation: 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.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Brillet
authors.affiliation: Institut des Sciences Analytiques, CNRS UMR5280, Université Lyon 1, École Nationale Supérieure de Lyon, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cala
authors.affiliation: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.|INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
authors.affiliation: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.|INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: William
authors.identifier: http://orcid.org/0000-0002-0643-7719
authors.initials: W
authors.lastname: Bourguet
authors.affiliation: Institut des Sciences Analytiques, CNRS UMR5280, Université Lyon 1, École Nationale Supérieure de Lyon, 5 rue de la Doua, 69100 Villeurbanne, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Krimm
authors.affiliation: 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.|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.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.affiliation: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.|INSERM U1054, Centre de Biochimie Structurale, Université de Montpellier, 29 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Guichou