Pseudoproline dipeptides are useful building blocks developed by Mutter for preparing long or difficult peptides (Mutter M., et al. Pept. Res. 1995, 8, 145, Wöhr T., et al. J. Am. Chem. Soc. 1996, 118, 9218, White P, et al., J. Pept. Sci. 2004, 10, 18.) In the peptide chain, the amide bond between the pseudoproline dipeptide and the preceding amino acid preferentially adopts a cis configuration. This creates a kink in the peptide backbone that prevents self-association, β-sheet formation and peptide aggregation. By disrupting aggregation and β-sheet formation, incorporation of pseudoproline dipeptides into peptides used for fragment condensation reactions can markedly improve solubility. The tendency for pseudoprolines to form a kink in the peptide backbone promotes cyclization of linear peptides. Park and coworkers (Page K, et al. J. Pept. Sci. 2007, 13, 833.) found that incorporating a pseudoproline dipeptide accelerated the on resin cyclization of linear amylin (1-13). Incorporation of pseudoproline dipeptides in the linear peptide promoted cyclization by ring closing metathesis (N. Schmiedeburg, H. Kessler, Org. Lett., 2002, 4(1), 59-62). In addition, C-terminal pseudoprolines eliminate the risk of epimerization at the C-terminal during fragment coupling.
Pseudoproline dipeptides are powerful tools for enhancing the synthesis of cyclic peptides, long peptides and “difficult” peptides, often enabling the production of peptides that otherwise were impossible or impractical to synthesize.
Guidelines for Using Pseudoproline Dipeptides
1. If possible, insert pseudoprolines before hydrophobic regions. 2. There should be at least 2 amino acids between pseudoprolines or between pseudoprolines and prolines. 3. The optimum spacing is 5-6 amino acids between pseudoprolines or between pseudoprolines and prolines.