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.