Structure-activity relationships of glucose-dependent insulinotropic polypeptide (GIP).
Six GIP(1-NH2) analogs were synthesized with modifications (de-protonation, N-methylation, reversed chirality, and substitution) at positions 1, 3, and 4 of the N-terminus, and additionally, a cyclized GIP derivative was synthesized. The relationship between altered structure to biological activity was assessed by measuring receptor binding affinity and ability to stimulate adenylyl cyclase in CHO-K1 cells transfected with the wild-type GIP receptor (wtGIPR). These structure-activity relationship studies demonstrate the importance of the GIP N-terminus and highlight structural constraints that can be introduced in GIP analogs. These analogs may be useful starting points for design of peptides with enhanced in vivo bioactivity.
Hinke
Simon A
SA
Department of Physiology, University of British Columbia, Vancouver, B.C., Canada V6T 1Z3.
Gelling
Rick
R
Manhart
Susanne
S
Lynn
Francis
F
Pederson
Raymond A
RA
Kühn-Wache
Kerstin
K
Rosche
Fred
F
Demuth
Hans-Ulrich
HU
Coy
David
D
McIntosh
Christopher H S
CH
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007328:Insulin; D010446:Peptide Fragments; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005947:Glucose