Dynamic combinatorial self-assembly of cyclophilin hCyp-18 ligands through oxorhenium coordination.
The dynamic combinatorial assembly of independent modules A and B through oxorhenium(V) coordination by a NS2+S motif in the presence of cyclophilin hCyp-18-an important peptidyl-prolyl isomerase-was investigated. Increasing glutathione (GSH) concentrations were used to dissociate [ARe(V)OB] complexes that displayed low affinity for hCyp-18. Conversely, coordinates that displayed submicromolar affinities for hCyp-18 were protected against thiol exchange and could be detected by LC-MS. Determination of the GSH concentration that decreased the extracted ionic current of the complex by 50 % (CC(50)) enabled the selection of three oxorhenium coordinates that were shown to bind to the active site of hCyp-18 and to inhibit its peptidyl-prolyl isomerase activity in the micromolar to submicromolar range.
Clavaud
Cécile
C
CEA, Institut de Biologie et de Technologie de Saclay (iBiTecS), Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), Bâtiment 152, 91191 Gif-sur-Yvette, France.
Le Gal
Julien
J
Thai
Robert
R
Moutiez
Mireille
M
Dugave
Christophe
C
D002853:Chromatography, Liquid; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D021983:Cyclophilins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D015203:Reproducibility of Results; D012211:Rhenium / Q000737:chemistry*; D013379:Substrate Specificity; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D008024:Ligands; C437224:cyclophilin hCyp-18; C015428:perrhenate; D012211:Rhenium; D021983:Cyclophilins; D005978:Glutathione