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Novel glycosylated VIP analogs: synthesis, biological activity, and metabolic stability

✍ Scribed by David Dangoor; Barbara Biondi; Marina Gobbo; Yelena Vachutinski; Mati Fridkin; Illana Gozes; Raniero Rocchi

Publisher
John Wiley and Sons
Year
2008
Tongue
English
Weight
189 KB
Volume
14
Category
Article
ISSN
1075-2617

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✦ Synopsis

Abstract

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.

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