Structure−Activity Studies of Ground- and Transition-State Analogue Inhibitors of Cyclophilin
| Autor: | Juris P. Germanas, Kyonghee Kim, Ray Bakhtiar, Harry C. Wang |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Magnetic Resonance Spectroscopy
Lactams Proline Stereochemistry Ligands Mass Spectrometry Cyclophilins Structure-Activity Relationship Transition state analog Cyclosporin a Drug Discovery Enzyme Inhibitors Cyclophilin Peptidylprolyl isomerase chemistry.chemical_classification Binding Sites biology Chemistry Indolizines Active site Stereoisomerism Spectrometry Fluorescence Enzyme Biochemistry Enzyme inhibitor Cis-trans-Isomerases biology.protein Molecular Medicine Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 44:2593-2600 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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