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Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents
Biopolymers, 2012, Vol.98 (5), p.443-450
Day, Jonathan W.
Gelfanov, Vasily
Smiley, David
Carrington, Paul E.
Eiermann, George
Chicchi, Gary
Erion, Mark D.
Gidda, Jas
Thornberry, Nancy A.
Tschöp, Matthias H.
Marsh, Donald J.
SinhaRoy, Ranabir
DiMarchi, Richard
Pocai, Alessandro
2012
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Day, Jonathan W.
Gelfanov, Vasily
Smiley, David
Carrington, Paul E.
Eiermann, George
Chicchi, Gary
Erion, Mark D.
Gidda, Jas
Thornberry, Nancy A.
Tschöp, Matthias H.
Marsh, Donald J.
SinhaRoy, Ranabir
DiMarchi, Richard
Pocai, Alessandro
Titel
Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents
Ist Teil von
Biopolymers, 2012, Vol.98 (5), p.443-450
Ort / Verlag
Hoboken: Wiley Subscription Services, Inc., A Wiley Company
Erscheinungsjahr
2012
Quelle
Access via Wiley Online Library
Beschreibungen/Notizen
The ratio of GLP‐1/glucagon receptor (GLP1R/GCGR) co‐agonism that achieves maximal weight loss without evidence of hyperglycemia was determined in diet‐induced obese (DIO) mice chronically treated with GLP1R/GCGR co‐agonist peptides differing in their relative receptor agonism. Using glucagon‐based peptides, a spectrum of receptor selectivity was achieved by a combination of selective incorporation of GLP‐1 sequences, C‐terminal modification, backbone lactam stapling to stabilize helical structure, and unnatural amino acid substitutions at the N‐terminal dipeptide. In addition to α‐amino‐isobutyric acid (Aib) substitution at position two, we show that α,α′‐dimethyl imidazole acetic acid (Dmia) can serve as a potent replacement for the highly conserved histidine at position one. Selective site‐specific pegylation was used to further minimize enzymatic degradation and provide uniform, extended in vivo duration of action. Maximal weight loss devoid of any sign of hyperglycemia was achieved with a co‐agonist comparably balanced for in vitro potency at murine GLP1R and GCGR. This peptide exhibited superior weight loss and glucose lowering compared to a structurally matched pure GLP1R agonist, and to co‐agonists of relatively reduced GCGR tone. Any further enhancement of the relative GCGR agonist potency yielded increased weight loss but at the expense of elevated blood glucose. We conclude that GCGR agonism concomitant with GLP1R agonism constitutes a promising approach to treatment of the metabolic syndrome. However, the relative ratio of GLP1R/GCGR co‐agonism needs to be carefully chosen for each species to maximize weight loss efficacy and minimize hyperglycemia. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 443–450, 2012.
Sprache
Englisch
Identifikatoren
ISSN: 0006-3525
eISSN: 1097-0282
DOI: 10.1002/bip.22072
Titel-ID: cdi_proquest_miscellaneous_1221848427
Format
–
Schlagworte
Amino Acid Sequence
,
Amino Acid Substitution
,
Aminoisobutyric Acids - chemistry
,
Animals
,
Anti-Obesity Agents - chemical synthesis
,
Anti-Obesity Agents - pharmacokinetics
,
Anti-Obesity Agents - standards
,
Blood Glucose - chemistry
,
Blood Glucose - drug effects
,
body weight
,
CHO Cells
,
co-agonist
,
Cricetinae
,
Cricetulus
,
Cyclic AMP - chemistry
,
GLP-1
,
glucagon
,
Glucagon-Like Peptide 1 - agonists
,
Glucagon-Like Peptide 1 - chemical synthesis
,
Glucagon-Like Peptide 1 - pharmacokinetics
,
Glucagon-Like Peptide-1 Receptor
,
glucose
,
Glucose - adverse effects
,
Glucose - chemistry
,
Glucose - pharmacology
,
Glycogenolysis
,
Histidine - chemistry
,
Humans
,
Hyperglycemia - drug therapy
,
Male
,
Mice
,
Mice, Inbred C57BL
,
Mice, Obese
,
Molecular Sequence Data
,
Proteolysis
,
Receptors, Glucagon - agonists
,
Receptors, Glucagon - chemistry
,
Structure-Activity Relationship
,
Transfection
,
Weight Loss
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