PSEUDO-PROLINES AS A MOLECULAR HINGE - REVERSIBLE INDUCTION OF CIS AMIDE BONDS INTO PEPTIDE BACKBONES

Serine, threonine-derived (4S)-oxazolidine-4-carboxylic acid, and cyst eine-derived (4R)-thiazolidinecarboxylic acid, denoted pseudo-proline (Xaa[Psi(R1,R2)pro]), serve as structure disrupting, solubilizing buil ding blocks in peptide synthesis. Variation of the 2-C substituents wi thin the heterocyclic system results in different physicochemical and conformational properties. NMR studies of a series of pseudo-proline ( Psi Pro)-containing peptides reveal a pronounced effect of the 2-C sub stituents upon the cis to trans ratio of the adjacent amide bond in so lution. 2-C unsubstituted systems show a preference similar to that of the proline residue for the trans form, whereas 2,2-dimethylated deri vatives adopt the cis amide conformation in high content. For 2-monosu bstituted Psi Pro, the cis-trans distribution depends on the 2-C chira lity. For the 2-(S)-diastereoisomer, both forms are similarly populate d in solution, whereas the 2-(R)-epimer adopts preferentially the tran s form. The results are supported by conformational energy calculation s and suggest that, by tailoring the degree of substitution, pseudo-pr olines may serve as a temporary proline mimetic or as a hinge in pepti de backbones.