Date of Award

January 2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Industrial and Physical Pharmacy

First Advisor

Elizabeth M Topp

Committee Member 1

Stephen R Byrn

Committee Member 2

Gregory T Knipp

Committee Member 3

Weiguo A Tao

Abstract

The biopharmaceutical industry has been growing at a tremendous rate, with sales of $63.6 billion 2012 in the US [1]. Nevertheless, the successful development of many protein drugs has been impeded by physical and chemical instabilities arising from their inherent chemical complexity and often leading to protein aggregation. The formation of non-native disulfide bonds is a common route to covalent aggregation of therapeutic proteins and other biologics [2, 3]. Disulfide bonds participate in hydrolytic and oxidative degradation reactions that form non-native disulfide bonds and other reactive species. The mechanisms responsible for protein aggregation are poorly understood and formulations are currently optimized on a trial and error basis. This approach contributes to high development costs and increases the time to market. The main goal of our research is to elucidate the mechanisms of thiol-disulfide exchange and disulfide scrambling in therapeutic proteins. To accomplish this goal, model peptides derived from human growth hormone (hGH) and intact hGH were used to investigate reaction mechanisms and kinetics in solution and solid-state environments. The results will be useful in the rational development of stable, safe and efficacious protein formulations that contain free cysteines and disulfides.

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