Novel analogs of VIP with multiple C-terminal domains.
The effect of multiplication of the N-terminal domain of vasoactive intestinal peptide (VIP) on the binding activity of the peptide was recently evaluated. A VIP analog with multiple N-terminal domains was found to be slightly more potent as compared to [Nle(17)]VIP towards VIP receptor type 1 (VPAC1)-related cAMP production. Here, the effect of multiplication of the C-terminal domain of VIP was evaluated with the aim of possibly amplifying peptide-receptor (VPAC1) binding and activation. Several VIP analogs were designed and synthesized, each carrying multiplication of the C-terminal domain that was obtained by either a simple linear tandem extension or by a unique branching methodology. Results show that despite significant alterations in the C-terminal domain of VIP that is considered essential to induce potent receptor binding, few peptides demonstrated only slight reduction in receptor binding and activation in comparison to [Nle(17)]VIP. Furthermore, a specific branched VIP analog with multiple C-terminal domains was equipotent to [Nle(17)]VIP in the cAMP production assay. Therefore, it is concluded that the association between the VIP ligand to the VIP receptor could be tolerable to size increases in the C-terminal region of the VIP ligand and multiplication of the C-terminal does not increase activity.
Dangoor
David
D
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Einstein Street, Tel Aviv 69978, Israel. dangoord@gmalil.com
Rubinraut
Sara
S
Fridkin
Mati
M
Gozes
Illana
I
D002942:Circular Dichroism; D000242:Cyclic AMP / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D018005:Receptors, Vasoactive Intestinal Peptide / Q000737:chemistry / Q000378:metabolism*
D010455:Peptides; D018005:Receptors, Vasoactive Intestinal Peptide; D000242:Cyclic AMP