Design and Evaluation of Peptide Dual-Agonists of GLP‑1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis

There is a critical unmet need for
therapeutics to treat the epidemic
of comorbidities associated with obesity and type 2 diabetes, ideally
devoid of nausea/emesis. This study developed monomeric peptide agonists
of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y2 receptor
(Y2-R) based on exendin-4 (Ex-4) and PYY3–36. A
novel peptide, GEP44, was obtained via in vitro receptor
screens, insulin secretion in islets, stability assays, and in vivo rat and shrew studies of glucoregulation, weight
loss, nausea, and emesis. GEP44 in lean and diet-induced obese rats
produced greater reduction in body weight compared to Ex-4 without
triggering nausea associated behavior. Studies in the shrew demonstrated
a near absence of emesis for GEP44 in contrast to Ex-4. Collectively,
these data demonstrate that targeting GLP-1R and Y2-R with chimeric
single peptides offers a route to new glucoregulatory treatments that
are well-tolerated and have improved weight loss when compared directly
to Ex-4.