Structure-activity relationship of synthetic truncated analogues of vasoactive intestinal peptide (VIP): an enhancement in the activity by a substitution with arginine.
In order to develop potent shortened analogues of vasoactive intestinal peptide (VIP), the structure-activity relationship of C-terminally truncated analogues of VIP was investigated by examining the binding activity to rat lung VIP receptors and relaxation of smooth muscle in isolated mouse stomach. VIP(1-27) showed VIP receptor binding activity comparable to that of VIP but the activity of VIP(1-26) was reduced to one-third of VIP. The receptor binding activity of VIP(1-26) to VIP(1-23) was reduced in proportion to the decrease in amino acid residues. There was a significant correlation between the number of amino acid residues and VIP receptor binding activities of VIP and its C-terminally truncated analogues. VIP(1-22) and VIP(1-21) exhibited little binding activity even at high concentrations, suggesting the requisite of 23 amino acid residues as the minimal essential sequence for the conservation of VIP receptor binding activity. The chemical modification of VIP(1-23) generated a potent analogue, [Arg(15, 20, 21), Leu(17)]-VIP(1-23), that displayed a 22-fold higher receptor binding activity and 1.6-fold more potent relaxation of mouse stomach than VIP(1-23) did. In conclusion, it was shown that [Arg(15, 20, 21), Leu(17)]-VIP(1-23) could be a relatively potent and stable agonist of VIP receptors. The present study has provided further insight into the structure-activity relationship of VIP to generate novel shortened VIP analogues having a high affinity to VIP receptors and potent pharmacological activity.
Onoue
Satomi
S
Health Science Division, Itoham Foods Inc., 1-2-1 Kubogaoka, Moriya, Ibaraki 302-0104, Japan.
Ohmori
Yuki
Y
Matsumoto
Asami
A
Yamada
Shizuo
S
Kimura
Ryohei
R
Yajima
Takehiko
T
Kashimoto
Kazuhisa
K
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D013270:Stomach / Q000033:anatomy & histology; D013329:Structure-Activity Relationship; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry / Q000378:metabolism*
D010446:Peptide Fragments; D014660:Vasoactive Intestinal Peptide; D001120:Arginine