SYNTHESIS OF PRO-RICH PEPTIDE ANALOGUE CONTAINING PIPECOLIC ACID: INFLUENCE ON PEPTIDE BOND STABILITY AND CONFORMATION

摘要

Pipecolic acid (Pip, piperidine-2-carboxylic acid) a naturally occurring, nonproteogenic α-imino acid, is a six-membered, piperidine ring based, proline analogue. It has been extensively used as proline substitute in numerous synthesis of peptido-mimetics and it has also been incorporated into a variety of bioactive peptides. Pipecolic acid has also been incorporated into proteins as a proline homologue in order to probe the role of ring size in structure and function. With the aim to study the influence of the ring steric hidrance in the Src homology 3 (SH3) mediated substrate recraiment we replaced all Pro residues into the HPK1 394-403 proline-rich sequence (PPPLPPKPKF), named P2, by pipecolic acid residues (Pip6). Surprisingly, this peptide is sensitive to the acidic conditions (90% TFA) used to cleavage the peptide from the Wang resin and to deprotect the Lys side chains. This is in stark contrast to acidic cleavage of proline-containing peptides accomplished under the same conditions. Our research aims to investigate the influence of the pipecolic residue on peptide bond stability to acidolysis, as well as and on peptide conformation.