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

Abdelhakim Ahmed-Belkacem (1) , Lionel Colliandre (2) , Nazim Ahnou (1) , Quentin Nevers (1) , Muriel Gelin (2) , Yannick Bessin (2, 3) , Rozenn Brillet (1) , Olivier Cala (4) , Dominique Douguet (2) , William Bourguet (2) , Isabelle Krimm (4) , Jean-Michel Pawlotsky (1, 5) , Jean-François Guichou (2)

1 IMRB - Institut Mondor de Recherche Biomédicale
2 CBS - Centre de Biochimie Structurale [Montpellier]
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
4 ISA - Méthodes et criblage RMN pour les molécules bioactives
5 Centre National de Référence Virus des hépatites B, C et Delta

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.

Mots clés: Antivirals; Pathogens; Structure-based drug design; MITOCHONDRIAL PERMEABILITY TRANSITION; T-CELL-ACTIVATION; CYCLOSPORINE-A; DRUG DISCOVERY; DESIGN; REPLICATION; ALISPORIVIR; MECHANISMS; APOPTOSIS; GENOTYPE

Domaines: Chimie analytique

Abdelhakim Ahmed-Belkacem, Lionel Colliandre, Nazim Ahnou, Quentin Nevers, Muriel Gelin, et al.. Fragment-based discovery of a new family of non-peptidic small-molecule cyclophilin inhibitors with potent antiviral activities. Nature Communications, 2016, 7, pp.Article Number: 12777. ⟨10.1038/ncomms12777⟩. ⟨hal-01397719⟩