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Novel glycosylated VIP analogs: synthesis, biological activity, and metabolic stability
Author(s) -
Dangoor David,
Biondi Barbara,
Gobbo Marina,
Vachutinski Yelena,
Fridkin Mati,
Gozes Illana,
Rocchi Raniero
Publication year - 2008
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.932
Subject(s) - vasoactive intestinal peptide , glycosylation , peptide , chemistry , receptor , biochemistry , trypsin , amino acid , neuropeptide , enzyme
Vasoactive intestinal peptide (VIP) is a prominent neuropeptide, exhibiting a wide spectrum of biological activities in mammals. However, the clinical applications of VIP are mainly hampered because of its rapid degradation in vivo . Peptide glycosylation, a procedure frequently used to increase peptide resistance to proteolytic degradation and consequently increase peptide metabolic stability, has not been performed yet on VIP. The presence of three N ‐glycosylation sites on VIP receptor type 1 (VPAC1) was previously demonstrated. Therefore, glycosylation of the VIP ligand could potentially increase its receptor affinity because of glyco–glyco interactions between the ligand and the receptor. In order to enhance VIP's metabolic stability and to increase its ligand–receptor binding/activation, eight glycosylated VIP derivatives were successfully synthesized by the solid‐phase procedure. Each VIP analog was monoglycosylated by a monosaccharide addition to one amino‐acid residue along the sequence. Glycosylation did not affect the α‐helical structure shown by the native VIP in organic environment. Few glycosylated VIP analogs displayed highly potent VPAC1 receptor binding and cAMP‐induced activation; only 4–6 fold lower in comparison to the native VIP. Furthermore, the peptide analog glycosylated on Thr 11 ([11Glyc]VIP) showed a significantly enhanced stability toward trypsin enzymatic degradation in comparison to VIP. Analysis of the degradation products of [11Glyc]VIP showed that differently from VIP, incubation of the peptide [11Glyc]VIP with trypsin resulted in no cleavage at the Arg 12 –Leu 13 peptide bond, suggesting that VIP glycosylation may lead to enhanced metabolic stability. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.