Date of Award

December 2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Robert P. Doyle

Subject Categories

Physical Sciences and Mathematics

Abstract

This thesis addresses three primary questions based on the pharmacodynamics (PD) or pharmacokinetics

(PK) of the diabetes drug exendin 4 (Ex-4), and vitamin B12 (B12) bioconjugates, thereof.

Q1. (Chapter 2) What effect does B12 conjugation to Ex-4 have on agonism of the glucagon-like peptide-1

receptor (GLP-1R) in vitro and on PD/PK (including brain uptake and function) in vivo?

Goal: To remove side-effects (nausea, weight loss) of Ex-4 without loss of glucoregulation.

Q2. (Chapter 3) Can B12 dietary uptake proteins such as gastric intrinsic factor offer protection to B12

conjugated peptides or proteins (focusing on Ex-4), with a view to improving in vivo PK?

Goal: To demonstrate (in vivo) that IF binding of B12-Ex-4 confers protection against gastric

proteolysis as a road-map to oral peptide delivery.

Q3. (Chapter 4) Can a dual agonist of the GLP-1R and neuropeptide Y2 receptor, based on the Ex-4 primary

amino acid sequence, be designed and validated in vitro and in vivo.

Goal: To create a new therapeutic to simultaneously treat diabetes and obesity.

Access

Open Access

Available for download on Saturday, July 28, 2018

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