Engineering of a Potent, Long-Acting NPY2R Agonist for Combination with a GLP-1R Agonist as a Multi-Hormonal Treatment for Obesity

Bariatric surgery
results in increased intestinal secretion of
hormones GLP-1 and anorexigenic PYY, which is believed to contribute
to the clinical efficacy associated with the procedure. This observation
raises the question whether combination treatment with gut hormone
analogs might recapitulate the efficacy and mitigate the significant
risks associated with surgery. Despite PYY demonstrating excellent
efficacy and safety profiles with regard to food intake reduction,
weight loss, and glucose control in preclinical animal models, PYY-based
therapeutic development remains challenging given a low serum stability
and half-life for the native peptide. Here, combined peptide stapling
and PEG-fatty acid conjugation affords potent PYY analogs with >14
h rat half-lives, which are expected to translate into a human half-life
suitable for once-weekly dosing. Excellent efficacy in glucose control,
food intake reduction, and weight loss for lead candidate 22 in combination with our previously reported long-acting GLP-1 analog
is demonstrated in a diet-induced obesity mouse model.