Glucagon, Glucagon-like Peptide-1 (GLP-1), and Glucose-dependent Insulinotropic Polypeptide (GIP) are regulatory hormones responsible for maintaining control of metabolism, most notably glucose homeostasis. We have developed a series of novel peptides which exhibit high potency and balanced activity across these three receptors. The quest for combinatorial efficacy across the traditional large/small molecule medicinal boundary has been explored through the use of incretin-based peptide conjugates with nuclear hormones. In metabolically-challenged non-diabetic mice, a fully active GLP-1 agonist with a stably-linked estrogen consistently proved to be more efficacious in lowering body weight than the comparable individual GLP-1 and estrogen controls. In addition, highly potent GLP-estrogen conjugates were found to be devoid of uterine hypertrophy. The molecular mechanism by which these beneficial effects are achieved remains a focus of our ongoing studies.

Multifunctional peptides targeting metabolic disease

244th National Meeting (2012)

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