title: Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents.
abstract: 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.
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Day
authors.forename: Vasily
authors.initials: V
authors.lastname: Gelfanov
authors.forename: David
authors.initials: D
authors.lastname: Smiley
authors.forename: Paul E
authors.initials: PE
authors.lastname: Carrington
authors.forename: George
authors.initials: G
authors.lastname: Eiermann
authors.forename: Gary
authors.initials: G
authors.lastname: Chicchi
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
authors.forename: Jas
authors.initials: J
authors.lastname: Gidda
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Ranabir
authors.initials: R
authors.lastname: SinhaRoy
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000621:Aminoisobutyric Acids / Q000737:chemistry; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000592:standards; D001786:Blood Glucose / Q000737:chemistry / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000737:chemistry; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D050261:Glycogenolysis; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D059748:Proteolysis; D018027:Receptors, Glucagon / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014162:Transfection; D015431:Weight Loss
chemical_list: D000621:Aminoisobutyric Acids; D019440:Anti-Obesity Agents; D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; C100049:2-aminoisobutyric acid; D006639:Histidine; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D005947:Glucose