title: Structural basis for the non-immunosuppressive character of the cyclosporin A analogue Debio 025.
abstract: Debio 025 is a cyclosporin A (CsA) analogue that interferes strongly with the hepatitis C viral life cycle. Compared to CsA, Debio 025 has an additional methyl group at position 3 of the cyclic undecapeptide and an N-ethylvaline instead of an N-methylleucine at position 4. Unlike CsA, Debio 025 lacks immunosuppressive activity in vitro and in vivo. We show here that, in vitro, the cyclophilin A (CypA)-Debio 025 complex cannot interact any longer with calcineurin (CaN), a determinant for the immunosuppressive activity of CsA. We further use NMR spectroscopy to investigate at the molecular level the interaction of Debio 025 with CypA and thereby understand the basis for this loss of CaN interaction. NMR data and molecular modeling indicate that Debio 025 optimally interacts with CypA, which underlies the anti-HCV properties of Debio 025. However, the interaction between CaN and the CypA-Debio 025 complex is impeded by sterical hindrance of the CaN with the side chain of its Val4 residue. This is in sharp contrast with the case for the CypA-CsA-CaN ternary complex, where the Leu4 side chain can enter a hydrophobic cavity at the CaN interface. The structure of the CypA-Debio 025 complex thus provides a rational explanation for the non-immunosuppressive character of Debio 025.
authors.affiliation: Structural and Functional Glycobiology Unit, UMR8576 CNRS-Université des Sciences et Technologies de Lille, Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Landrieu
authors.forename: Xavier
authors.initials: X
authors.lastname: Hanoulle
authors.forename: Fanny
authors.initials: F
authors.lastname: Bonachera
authors.forename: Arnaud
authors.initials: A
authors.lastname: Hamel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sibille
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Yin
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Wieruszeski
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vuagniaux
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry* / Q000378:metabolism; D004347:Drug Interactions; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D007930:Leucine; D014633:Valine; C499715:alisporivir