Date Available
10-14-2015
Year of Publication
2015
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Anatomy and Neurobiology
First Advisor
Dr. Greg A. Gerhardt
Second Advisor
Dr. John M. Littleton
Abstract
The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity at this therapeutic target, i.e. the human DAT. This was achieved by expressing the human DAT protein in transgenic plant cells and selecting gain-of-function mutants for survival on medium containing a neurotoxin that is accumulated by the human DAT. This created a sub-population of mutants with increased DAT inhibitory activity. Some of the active metabolites in these mutants are novel (i.e. not detectable in wild-type cells). Others are cytoprotective, and also protect DAergic neurons against the neurotoxin. This provides proof-of-concept for a novel plant drug discovery platform, which is applicable to many different therapeutic target proteins and plant species.
Recommended Citation
Brown, Dustin Paul, "TARGET-DIRECTED BIOSYNTHETIC EVOLUTION: REDIRECTING PLANT EVOLUTION TO GENOMICALLY OPTIMIZE A PLANT’S PHARMACOLOGICAL PROFILE" (2015). Theses and Dissertations--Neuroscience. 13.
https://uknowledge.uky.edu/neurobio_etds/13
Included in
Agricultural Science Commons, Alternative and Complementary Medicine Commons, Biomedical Engineering and Bioengineering Commons, Biotechnology Commons, Chemical Actions and Uses Commons, Complex Mixtures Commons, Evolution Commons, Genomics Commons, Heterocyclic Compounds Commons, Lipids Commons, Medicinal and Pharmaceutical Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Natural Products Chemistry and Pharmacognosy Commons, Nervous System Commons, Organic Chemicals Commons, Pharmaceutics and Drug Design Commons, Polycyclic Compounds Commons, Psychiatry and Psychology Commons
