Title

Improving access to biologically and pharmaceutically relevant molecules by understanding mechanisms of biosynthesis and improving chemical synthesis

Date of Award

2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Keywords

Laulimalides, Sialic acid, Tenofovir, Escherichia coli BL21(PL3), Drug development, Polyketides

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

The development of innovative strategies to produce complex bioactive molecules in quantities necessary for drug development, diagnostics, or research tools is a challenging endeavor. The process must be efficient, commercially feasible, and environmentally sustainable to be considered viable for development. Biotechnology offers promise as an efficient mechanism of drug manufacturing. By utilizing a diverse portfolio of chemical and biological tools (biosynthesis, fermentation, genetic engineering, and chemical synthesis) access to pharmaceutically and biologically significant molecules becomes a reality. Exploring the biosynthesis of natural products such as laulimalide, offers an alternative methodology to chemical synthesis for application as an anticancer agent. Fermentation-based strategies to produce sialic acid have been realized and the in vitro enzymatic pathway presented here provides insight to improve its yield. Genetic engineering of bacterial protein expression strains such as E. coli BL21(DE3) can provide improved metabolism capable of increased utilization of carbon sources or incorporation of inexpensive isotopically labeled substrates into proteins. Synthesis of drugs in a manufacturing setting such as tenofovir require efficient, cost-effective, and robust synthetic methodologies to have an impact on the cost of the drug in the marketplace. These strategies represent a new set of interdisciplinary drug development tools capable of providing more efficacious and affordable drugs to the public.

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