Structural basis for the non-immunosuppressive character of the cyclosporin A analogue Debio 025.
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.
Landrieu
Isabelle
I
Structural and Functional Glycobiology Unit, UMR8576 CNRS-Université des Sciences et Technologies de Lille, Lille, France.
Hanoulle
Xavier
X
Bonachera
Fanny
F
Hamel
Arnaud
A
Sibille
Nathalie
N
Yin
Yanxia
Y
Wieruszeski
Jean-Michel
JM
Horvath
Dragos
D
Wei
Qun
Q
Vuagniaux
Grégoire
G
Lippens
Guy
G
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
D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; D007930:Leucine; D014633:Valine; C499715:alisporivir