title: Ranking high affinity ligands of low solubility by NMR spectroscopy.
abstract: Cyclosporine A (CsA) and its chemical analogues EthVal4Cs, MeVal4Cs, and Me(d-Ala)3EthVal4Cs (Alisporivir) all interact with cyclophilin A (CypA). The latter Alisporivir is a nonimmunosuppressive CsA derivative that has potent anti-HCV properties in clinical trials. We show here that NMR spectroscopy can be used to rank this series of related pharmacological molecules despite their high affinity for the target protein and low solubility in water. The novel method is based on the possibility to detect distinct NMR signals from the different protein complexes in a mixture. The method has enabled us to distinguish subtle effects of discrete chemical modifications of the parent molecule on the affinity of the ligands for the target protein.
authors.affiliation: CNRS-UMR 8576, UGSF-IFR 147, Université des Sciences et Technologies de Lille , 59655 Villeneuve d'Ascq Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Landrieu
authors.affiliation: CNRS-UMR 8576, UGSF-IFR 147, Université des Sciences et Technologies de Lille , 59655 Villeneuve d'Ascq Cedex, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Hanoulle
authors.affiliation: CNRS-UMR 8576, UGSF-IFR 147, Université des Sciences et Technologies de Lille , 59655 Villeneuve d'Ascq Cedex, France.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzinger
authors.affiliation: ECNRS, UMR 7177, Laboratoire d'Infochimie, Université de Strasbourg , 67000 Strasbourg, France.
authors.forename: Dragos
authors.initials: D
authors.lastname: Horvath
authors.affiliation: CNRS-UMR 8576, UGSF-IFR 147, Université des Sciences et Technologies de Lille , 59655 Villeneuve d'Ascq Cedex, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Wieruszeski
authors.affiliation: CNRS-UMR 8576, UGSF-IFR 147, Université des Sciences et Technologies de Lille , 59655 Villeneuve d'Ascq Cedex, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
keywords: Alisporivir; Nuclear magnetic resonance; cyclophilin A; ligands; proteins