title: Improved glucose control and reduced body weight in rodents with dual mechanism of action peptide hybrids.
abstract: Combination therapy is being increasingly used as a treatment paradigm for metabolic diseases such as diabetes and obesity. In the peptide therapeutics realm, recent work has highlighted the therapeutic potential of chimeric peptides that act on two distinct receptors, thereby harnessing parallel complementary mechanisms to induce additive or synergistic benefit compared to monotherapy. Here, we extend this hypothesis by linking a known anti-diabetic peptide with an anti-obesity peptide into a novel peptide hybrid, which we termed a phybrid. We report on the synthesis and biological activity of two such phybrids (AC164204 and AC164209), comprised of a glucagon-like peptide-1 receptor (GLP1-R) agonist, and exenatide analog, AC3082, covalently linked to a second generation amylin analog, davalintide. Both molecules acted as full agonists at their cognate receptors in vitro, albeit with reduced potency at the calcitonin receptor indicating slightly perturbed amylin agonism. In obese diabetic Lep(ob)/Lep (ob) mice sustained infusion of AC164204 and AC164209 reduced glucose and glycated haemoglobin (HbA1c) equivalently but induced greater weight loss relative to exenatide administration alone. Weight loss was similar to that induced by combined administration of exenatide and davalintide. In diet-induced obese rats, both phybrids dose-dependently reduced food intake and body weight to a greater extent than exenatide or davalintide alone, and equal to co-infusion of exenatide and davalintide. Phybrid-mediated and exenatide + davalintide-mediated weight loss was associated with reduced adiposity and preservation of lean mass. These data are the first to provide in vivo proof-of-concept for multi-pathway targeting in metabolic disease via a peptide hybrid, demonstrating that this approach is as effective as co-administration of individual peptides.
authors.affiliation: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
authors.forename: James L
authors.initials: JL
authors.lastname: Trevaskis
authors.forename: Christine M
authors.initials: CM
authors.lastname: Mack
authors.forename: Chengzao
authors.initials: C
authors.lastname: Sun
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Soares
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: D'Souza
authors.forename: Odile E
authors.initials: OE
authors.lastname: Levy
authors.forename: Diane Y
authors.initials: DY
authors.lastname: Lewis
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Jodka
authors.forename: Krystyna
authors.initials: K
authors.lastname: Tatarkiewicz
authors.forename: Bronislava
authors.initials: B
authors.lastname: Gedulin
authors.forename: Swati
authors.initials: S
authors.lastname: Gupta
authors.forename: Carrie
authors.initials: C
authors.lastname: Wittmer
authors.forename: Michael
authors.initials: M
authors.lastname: Hanley
authors.forename: Bruce
authors.initials: B
authors.lastname: Forood
authors.forename: David G
authors.initials: DG
authors.lastname: Parkes
authors.forename: Soumitra S
authors.initials: SS
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose; D006442:Glycated Hemoglobin; D010455:Peptides; D018027:Receptors, Glucagon; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; C558406:HbA(1c) protein, mouse