Novel extended and branched N-terminal analogs of VIP.
The effects of vasoactive intestinal peptide (VIP) are primarily mediated through VPAC1 and VPAC2, receptors that are preferentially coupled to adenylate cyclase activation. As a large majority of the potent VIP antagonists have modifications in the N-terminal domain of the peptide, the effect of multiplication of this domain on VIP was examined with the aim of possibly amplifying peptide-receptor (VPAC1) activation. Several VIP analogs were designed and synthesized, each carrying multiplication of the N-terminal domain that was obtained by either linear tandem extension or by parallel branching. Circular dichorism (CD) analysis revealed that these extended/branched peptides maintained an alpha helical structure in organic environment, similar to VIP. A specific branched VIP analog was found to be slightly more potent towards VPAC1-related cAMP production as compared to VIP. This analog could have potential therapeutic value in several disorders, similar to VIP. Two branched N-terminal VIP sequences demonstrated superior receptor binding and activation as compared to two N-terminals in tandem. The results suggest that correct alignment of the VIP N-terminal region is important for receptor binding and activation. However, increased receptor binding was not directly associated with increased cAMP production suggesting steric dynamic interactions.
Dangoor
David
D
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Einstein Street, Tel Aviv 69978, Israel.
Rubinraut
Sara
S
Fridkin
Mati
M
Gozes
Illana
I
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D000242:Cyclic AMP / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D008969:Molecular Sequence Data; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000737:chemistry
D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP