Enhancing the proline effect: Pseudo-prolines for tailoring cis/trans isomerization

Cis-trans isomerization of proline-like oxazolidines and thiazolidines, denoted pseudo-prolines, is investigated spectrophotometrically with a chymotrypsin coupled assay and by H-1 NMR. A series of peptides carrying substituents of varying stereochemistry at the 2-C position of Psi Pro was prepared for evaluating kinetic and thermodynamic data pertaining to the isomerization of the imidic bond. Psi Pro are shown to exhibit an enhanced proline effect, allowing the cis content along the imide bond to be tailored between 5 and about 100%. These Pro surrogates may serve as beta-turn type VI mimetics and can be used to introduce specifically cis-imide bonds into peptides and proteins. Psi Pro derived from Ser and Thr show a marked difference in the rate of isomerization about the imide bond compared to Cys derived thiazolidines. As with Pro itself, the cis content for the (S) epimers of oxazolidines and thiazolidines can be raised from about 40-60% using LiCl/TFE as a solvent, allowing more accurate measurements of the isomerization kinetics. In general, peptides containing Psi Pro exhibit enhanced isomerization rate constants for cis/trans isomerization compared to their proline analogues depending on stereochemistry and degree of substitution at the 2-C Psi Pro position. For example, the thermodynamic barrier of the isomerization process for 2-C dimethylated Psi Pro is decreased by about 2-4.kcal/mol in comparison to Pro. In summary, Psi Pro represent versatile Pro surrogates enhancing the conformational and structural effects of Pro and offer a wide range of applications in peptide design and engineering.

Published in:
J. Am. Chem. Soc., 120, 12, 2714-2720

 Record created 2006-02-09, last modified 2018-01-27

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