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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125182
    Cyclophilin/HCV 抑制剂
    HCV
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