ADVANCEMENTS IN GLYCOMETABOLIC ENGINEERING AND CARBOHYDRATE DRUG DESIGN

Abstract

A near universal feature of virtually every major disease in humans has been the observation that proteins and lipids have perturbed patterns of glycosylation when compared to healthy tissues and cells, indicating that a disturbance of the glycome is correlated with disease progression and development. Glycosylation has now been shown to have fundamental roles in the regulation of the immune system and host-pathogen recognition, directing processes during development, and serves as a marker more accurate than even telomeres for assessing both biological and chronological age. Indeed, glycobiology has been labeled as one of the top fields that will revolutionize medicine in the 21st century.

While the genomic revolution has provided a wealth of information about genes and DNA, the study of carbohydrates and glycans, now known as the field of ‘glycobiology’, has been sluggish to yield similarly impressive results largely due to the fact that many of the sequencing and molecular tools available to study genes and proteins simply does not exist for the glycobiologist. In order to address the shortcomings of the research tools available to the glycobiology community, an approach known as ‘metabolic glycoengineering’ (MGE) began to be developed in the 1990s and has now served as a fundamental cornerstone in unlocking the secrets of the glycome for nearly thirty years.

The work in this thesis describes efforts to help translate MGE tools by applying drug design principles to profile their physiochemical, toxicity, and (absorption, distribution, metabolism and excretion) ADME properties. Next, a modern application of MGE is used to discover novel insights into breast cancer cell subtype based on their sialic acid metabolism and to identify glycoprotein markers which have altered sialylation in response to changes in metabolic flux. Finally, the glycometabolic enzyme UAP1/2 is identified as an intriguing cancer drug target. We attempt to show that UAP1/2 can be drugged with carbohydrate mimetics, and in an additional chapter, show that this enzyme has a critical role in regulation of the Hippo-Tumor Suppressor Pathway in glioblastoma. These findings aid in advancing the translation of techniques and applications of MGE and carbohydrate drug design for applications in the treatment of cancer.