Glycated cholecystokinin-8 has an enhanced satiating activity and is protected against enzymatic degradation.
Monoglycated cholecystokinin octapeptide (CCK-8) (glucitol-Asp1 adduct) modified at the NH2-terminus was prepared under hyperglycemic conditions, purified by high-performance liquid chromatography, and characterized by mass spectrometry (Mr 1228.4 Da) and peptide sequencing. CCK-8 (100 nmol/kg, i.p.) significantly (P < 0.001) reduced voluntary food intake of fasted mice for up to 30 min after its administration, compared with saline-administered controls. Glycated CCK-8 reduced food intake at 30-120 min (P < 0.01 to P < 0.001) and significantly reduced feeding compared with CCK-8 from 60 to 120 min (P < 0.01). In vitro plasma degradation studies indicated that glycated CCK-8 was resistant to the normal rapid enzymatic conversion to CCK fragments. This study demonstrated that CCK-8 is a potent short-term inhibitor of food intake, and that structural modification of this peptide by amino-terminal glycation leads to enhanced satiating activity, partially due to increased resistance to serum aminopeptidase degradation.
O'Harte
F P
FP
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland. fpm.oharte@ulst.ac.uk
Mooney
M H
MH
Kelly
C M
CM
Flatt
P R
PR
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D001769:Blood; D004435:Eating / Q000187:drug effects*; D006031:Glycosylation; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism; D012527:Satiation / Q000187:drug effects*; D017421:Sequence Analysis; D012844:Sincalide / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013012:Sorbitol / Q000737:chemistry*; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D013012:Sorbitol; D000626:Aminopeptidases; D012844:Sincalide