Date of Award
6-26-2026
Date Published
August 2026
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
Advisor(s)
Robert Doyle
Subject Categories
Chemistry | Physical Sciences and Mathematics
Abstract
Obesity and metabolic dysfunction contribute to a wide spectrum of chronic diseases and represent major global health challenges. Pharmacotherapies targeting glucagon-like peptide 1 receptor (GLP-1R) effectively reduce body weight and improve glycemic control, but these agents are frequently associated with malaise, nausea, vomiting and gastrointestinal adverse events. Emerging evidence also suggests that certain GLP-1R agonists may reduce lean muscle mass and exhibit diminished efficacy over prolonged treatment (>6 months on a set dose). Consequently, there remains a clinical unmet need for obesity therapeutics that provide sustained metabolic benefits with improved tolerability. The work herein investigates the therapeutic potential of simultaneously targeting multiple hindbrain receptors involved in energy homeostasis in a polypharmacy approach. We evaluated the effects of subcutaneous administration of our novel multiple agonists in diet-induced obese rats, assessing effects on body weight and energy intake. In chapters 2 and 3, we demonstrate that the peptides KCEM1, GG3, and GG6 not only reduced food intake and body weight at levels comparable to clinically approved GLP-1R agonists but do so without inducing conditioned taste aversion in mice or visceral malaise in musk shrews at functional doses. In chapter 4, we outline that the peptide SU37 functions as a potential antagonist of GPR75, an orphan receptor targeted for protection from obesity, resulting in resistance of weight gain in mice maintained on high-fat diet. Collectively, these findings demonstrate the feasibility of rationally designing peptide multiple agonists to achieve complimentary effects while concomitantly minimizing adverse events. This work highlights the development and pre-clinical translational evaluation of multi-target therapeutics for metabolic disease to produce weight-loss devoid of adverse gastrointestinal events and lean muscle mass loss.
Access
Open Access
Recommended Citation
Ashlaw, Emily, "Design, Synthesis, and Characterization of Monomeric Peptide Multiple Agonists for the Treatment of Metabolic Disease" (2026). Dissertations - ALL. 2363.
https://surface.syr.edu/etd/2363
