Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects

The effects of oxytocin on food intake and body weight
reduction
have been demonstrated in both animal models and human clinical studies.
Despite being efficacious, oxytocin is enzymatically unstable and
thus considered to be unsuitable for long-term use in patients with
obesity. Herein, a series of oxytocin derivatives were engineered
through conjugation with fatty acid moieties that are known to exhibit
high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin
receptor (OTR) in vitro with good selectivity and long half-life (24
h) in mice. Furthermore, OT-12 is peripherally restricted,
with very limited brain exposure (1/190 of the plasma level). In a
diet-induced obesity mouse model, daily subcutaneous administration
of OT-12 exhibited more potent anorexigenic and body
weight reducing effects than carbetocin. Thus, our results suggest
that the long-acting, peripherally restricted OTR agonist may offer
potential therapeutic benefits for obesity.