Synthesis and Evaluation of Glycosylated Oxytocin Analogues for Treating Pain and Substance Use Disorder
PublisherThe University of Arizona.
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AbstractPeptide drugs are a promising alternative to classical small molecule therapeutics with various applications, ranging from antibiotic resistant infection to prostate cancer. Despite their increased safety profile relative to most small molecule drugs, they are poor candidates based on the pharmacokinetic properties from their peptide nature. Several strategies have been proposed to overcome these limitations, among them glycosylation. Oxytocin, a pleotropic neurohormone conserved across species for 700 million years, is involved in a range of fundamental physiological processes, making it particularly appealing as a multifunctional therapeutic. Implemented clinically for over a century, its daily use continues, and its value is affirmed by its placement on the World Health Organization’s model list of essential medicines for treatment of postpartum hemorrhage. Despite this significance, broader pharmaceutic application remains hindered by its short half-life, minimal blood-brain barrier (BBB) penetration, and receptor promiscuity. The inability to make oxytocin a widely useful therapeutic after more than a century of clinical implementation is exemplary of the promise and limitations of peptide drugs. We have applied common synthetic strategies for improving the “druggability” of peptide drugs (e.g., cyclization, glycosylation) to generate robust, BBB penetrant, receptor selective oxytocin analogues. Pulsed field gradient (PFG) Nuclear Magnetic Resonance (NMR) Spectroscopy has been used to optimize delivery of these candidates from glycolipid micelles. Insights into molecular mechanisms of drug delivery, including micellar incorporation, dissociation, and controlled release of glycopeptide drug candidates, are supported by molecular modeling. The aim was to develop a novel platform capable of application to other glycopeptide candidates to deliver on the therapeutic promise of glycopeptide drugs.
Degree ProgramGraduate College