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

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.

• Authors: Brandon T Milliken, Clinton Elfers, Oleg G Chepurny, Kylie S Chichura, Ian R Sweet, Tito Borner, Matthew R Hayes, Bart C De Jonghe, George G Holz, Christian L Roth, Robert P Doyle
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 2 Pg. 1127-1138 (01 28 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33449689 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Blood Glucose
• Glucagon-Like Peptide-1 Receptor
• Receptors, Neuropeptide Y
• neuropeptide Y2 receptor
• Peptide YY
• Exenatide
• Glucose

Topics

• Animals
• Binding, Competitive
• Blood Glucose (metabolism)
• Exenatide (chemistry)
• Glucagon-Like Peptide-1 Receptor (agonists)
• Glucose (metabolism)
• Humans
• Insulin Secretion (drug effects)
• Islets of Langerhans (drug effects, metabolism)
• Male
• Microsomes, Liver (metabolism)
• Models, Molecular
• Molecular Docking Simulation
• Nausea (drug therapy)
• Peptide YY (chemistry)
• Rats
• Rats, Sprague-Dawley
• Receptors, Neuropeptide Y (agonists)
• Shrews
• Structure-Activity Relationship
• Vomiting (drug therapy)
• Weight Loss (drug effects)