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| - Synthesis and Biological Activity of the Prodrug of Class I MajorHistocompatibility Peptide GILGFVFTL Activated by β-Glucuronidase
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| - The first synthesis of a prodrug of HLA-A2.1 associated antigenic influenza peptide 2a wasaccomplished. Two methods for synthesis of prodrugs of antigenic peptides activated byβ-glucuronidase and comprising a self-immolative 3-nitrobenzyloxycarbonyl moiety wereinvestigated. Reaction of β-glucuronic acid glycoside of 4-hydroxy-3-nitrobenzyl alcohol (3) withN,N‘-disuccinimidyl carbonate (DSC) followed by conjugation with AlaOMe, Gly, Thr, Phe-Leu, and Leu-Arg gave carbamates 4a−4f. Deacetylation of 4b and 4e with MeONa/MeOHgave β-glucuronides 5b and 5e. Compound 5e was converted to β-glucuronic acid conjugate 6eby the action of pig liver esterase (PLE). Compound 6e is a substrate for β-glucuronidase.Method of a direct introduction of the prodrug residue into antigenic nonapeptide GILGFVFTL(2b) failed. Alternately, glycine conjugate 5b was activated to pentafluorophenyl ester 10. Modelcoupling of 10 with Phe-Leu gave tripeptide conjugate ester 11a which was hydrolyzed by PLEto uronic acid 12. Condensation of 10 with octapeptide ILGFVFTL (9) gave prodrug precursor11b. Octapeptide 9 was prepared by de novo synthesis using a racemization-free fragmentcoupling method. Ester hydrolysis with Ba(OH)2/MeOH gave the target prodrug 2a which is asubstrate for β-glucuronidase. Prodrug 2a does not bind to HLA-A2.1 of T2 human cells defectivein major histocompatibility complex I (MHC I)-associated peptide processing. Addition ofβ-glucuronidase restored the binding to the level observed with parent nonapeptide 2b althoughhigher concentrations of prodrug 2a and enzyme were necessary.
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