Structure-activity studies of ground- and transition-state analogue inhibitors of cyclophilin.

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Wang HC, Kim K, Bakhtiar R, Germanas JP

Structure-activity studies of ground- and transition-state analogue inhibitors of cyclophilin.

J Med Chem. 2001 Aug 2;44(16):2593-600.

PubMed ID

11472213 [ View in PubMed

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Abstract

Peptidyl-prolyl isomerases (PPIases) are ubiquitous cellular enzymes that play roles in cellular signaling and protein folding. In addition, these proteins are the receptors for the widely used immunosuppressants cyclosporin A and FK506. We report the first structure-activity studies of de novo designed inhibitors of cyclophilin, the cellular target of cyclosporin A. Our mechanism-based inhibitors were modeled on the ground- and transition-state structures of proline-containing peptides, the natural substrates of the enzyme. Both ground-state analogues 1 and transition-state analogues 2 were prepared as single enantiomers from L-proline following a "self-reproduction of chirality" procedure. The binding affinities of the analogues for the active site of cyclophilin were measured by a fluorescence perturbation assay. While the transition-state analogues 2 did not display significant avidity for the active site (K(d) = 77 microM for 2b), several ground-state analogues bound to the enzyme with low micromolar affinity (K(d) = 1.5 microM for 1e). These results proclaim that properly designed small molecular weight molecules can form strong complexes with cyclophilin and may find use as probes in cell biology and as therapeutic agents.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Cyclosporine	Peptidyl-prolyl cis-trans isomerase A	Kd (nM)	300	N/A	N/A	Details