Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis.
Brandon T MillikenClinton ElfersOleg G ChepurnyKylie S ChichuraIan R SweetTito BornerMatthew R HayesBart C De JongheGeorge G HolzChristian L RothRobert P DoylePublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- weight loss
- bariatric surgery
- roux en y gastric bypass
- chemotherapy induced
- type diabetes
- body weight
- glycemic control
- gastric bypass
- high throughput
- weight gain
- magnetic resonance
- obese patients
- insulin resistance
- case control
- genome wide
- oxidative stress
- magnetic resonance imaging
- mesenchymal stem cells
- binding protein
- adipose tissue
- cancer therapy
- cell therapy
- bone mineral density
- body mass index
- physical activity
- drug delivery
- machine learning
- postmenopausal women
- gene expression
- big data
- bone marrow