Abstract

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.

Highlights

  • Comorbidities associated with obesity and type 2 diabetes (T2D) continue to be great health challenges with the global population seeing rising child and adult obesity and diabetes rates.[1,2] Pharmacotherapies targeting gut peptide signaling pathways, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), arguably show the greatest promise for the treatment of comorbidities associated with obesity and T2D

  • Initial GLP-1RAs prescribed for the management of T2D produced modest weight loss that was associated with nausea in 20−50% of patients.[10−15] More recently, GLP1RAs such as liraglutide and semaglutide have shown significant improvements in weight loss relative to earlier analogues, semaglutide is currently only prescribed for T2D treatment

  • An alternative approach involves targeting two or more signaling pathways with the same molecule such as monomeric multiagonists based on GLP-1 and glucagon,[17−20] or GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), with[21] and without[22] glucagon receptor (GlucR) agonism

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Summary

Introduction

Comorbidities associated with obesity and type 2 diabetes (T2D) continue to be great health challenges with the global population seeing rising child and adult obesity and diabetes rates.[1,2] Pharmacotherapies targeting gut peptide signaling pathways, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), arguably show the greatest promise for the treatment of comorbidities associated with obesity and T2D. Drug combinations (e.g., phentermine + topiramate, naltrexone + bupropion) achieve stronger reductions of body weight compared to monotherapy with either component individually.[16] An alternative approach involves targeting two or more signaling pathways with the same molecule such as monomeric multiagonists based on GLP-1 and glucagon,[17−20] or GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), with[21] and without[22] glucagon receptor (GlucR) agonism. Such novel therapies show considerable promise, nausea/emesis and GI side effects in general continue to be unwanted factors.[23]

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