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

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 () and Jean- François Guichou ()
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Abdelhakim Ahmed-Belkacem: INSERM U955 ‘Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers’, Hôpital Henri Mondor, Université Paris-Est
Lionel Colliandre: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier
Nazim Ahnou: INSERM U955 ‘Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers’, Hôpital Henri Mondor, Université Paris-Est
Quentin Nevers: INSERM U955 ‘Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers’, Hôpital Henri Mondor, Université Paris-Est
Muriel Gelin: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier
Yannick Bessin: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier
Rozenn Brillet: INSERM U955 ‘Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers’, Hôpital Henri Mondor, Université Paris-Est
Olivier Cala: Institut des Sciences Analytiques, CNRS UMR5280, Université Lyon 1, École Nationale Supérieure de Lyon
Dominique Douguet: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier
William Bourguet: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier
Isabelle Krimm: Institut des Sciences Analytiques, CNRS UMR5280, Université Lyon 1, École Nationale Supérieure de Lyon
Jean-Michel Pawlotsky: INSERM U955 ‘Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers’, Hôpital Henri Mondor, Université Paris-Est
Jean- François Guichou: CNRS UMR5048, Centre de Biochimie Structurale, Université de Montpellier

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12777

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