title: Incorporation of N-amidino-pyroglutamic acid into peptides using intramolecular cyclization of alpha-guanidinoglutaric acid.
abstract: N-terminal modification of peptides by unnatural amino acids significantly affects their enzymatic stability, conformational properties and biological activity. Application of N-amidino-amino acids, positively charged under physiological conditions, can change peptide conformation and its affinity to the corresponding receptor. In this article, we describe synthesis of short peptides, containing a new building block-N-amidino-pyroglutamic acid. Although direct guanidinylation of pyroglutamic acid and oxidation of N-amidino-proline using RuO(4) did not produce positive results, N-amidino-Glp-Phe-OH was synthesized on Wang polymer by cyclization of alpha-guanidinoglutaric acid residue. In the course of synthesis, it was found that literature procedure of selective Boc deprotection using TMSOTf/TEA reagent is accompanied by concomitant side reaction of triethylamine alkylation by polymer linker fragment. It should be mentioned that independently from cyclization time and coupling agent (DIC or HCTU), the lactam formation was incomplete. Separation of the cyclic product from the linear precursor was achieved by HPLC in ammonium formate buffer at pH 6. HPLC analysis showed N-amidino-Glp-Phe-OH stability at acidic and physiological pH and fast ring opening in water solution at pH 9. The suggested method of N-amidino-Glp residue formation can be applied in the case of short peptide chains, whereas synthesis of longer ones will require fragment condensation approach.
authors.affiliation: Institute of Macromolecular Compounds RAS, 199004, St Petersburg, Russia. burov@hq.macro.ru
authors.forename: Sergey
authors.initials: S
authors.lastname: Burov
authors.forename: Yulia
authors.initials: Y
authors.lastname: Moskalenko
authors.forename: Marina
authors.initials: M
authors.lastname: Dorosh
authors.forename: Zoya
authors.initials: Z
authors.lastname: Shkarubskaya
authors.forename: Evgeny
authors.initials: E
authors.lastname: Panarin
mesh_terms: D002851:Chromatography, High Pressure Liquid; D005977:Glutarates / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry*; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*
chemical_list: D005977:Glutarates; D010455:Peptides; C028262:alpha-guanidinoglutaric acid; D011761:Pyrrolidonecarboxylic Acid