Engineering of a VPAC2 receptor peptide agonist to impart dipeptidyl peptidase IV stability and enhance in vivo glucose disposal.
VPAC2P-PEG is a VPAC2 receptor agonist peptide that acts as a glucose-dependent insulin secretagogue. Proteolysis by DPPIV may contribute to the in vivo clearance of VPAC2P-PEG. Here, the N-terminus of VPAC2P-PEG is modified by N-terminal acetylation to impart DPPIV resistance. The acetylated peptide, Ac-VPAC2P-PEG, is a selective and potent VPAC2 agonist, resistant to DPPIV proteolysis, and exhibits substantially improved half-life and glucose disposal in rodents. Ac-VPAC2P-PEG has therapeutic potential for diabetes management.
Clairmont
Kevin B
KB
Department of Metabolic Disorders Research, Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, Connecticut 06516, USA.
Buckholz
Thomas M
TM
Pellegrino
Carla M
CM
Buxton
Joanne M
JM
Barucci
Nicole
N
Bell
Andrea
A
Ha
Sha
S
Li
Fugang
F
Claus
Thomas H
TH
Salhanick
Arthur I
AI
Lumb
Kevin J
KJ
D000107:Acetylation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists* / Q000378:metabolism
D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D018819:Dipeptidyl Peptidase 4; D005947:Glucose