Research & Interests
Enzymes involved in nucleic acid biosynthesis are a major focus of my lab's research. We are primarily interested in the structure to function relationship of enzymes that catalyze the formation of precursors for DNA and RNA and, most notably, also convert nucleoside analogs or prodrugs to cytotoxic compounds. Using several mutagenesis and molecular strategies we target these enzymes and select for variants with altered activities towards the nontoxic prodrugs. Biochemical evaluation along with in vitro and in vivo analysis of derived mutants that display enhanced prodrug activation allows the identification of mutants for use in gene therapy for the treatment of cancer. In a process known as suicide gene therapy, a nucleoside metabolizing gene is delivered to a cancer cell followed by administration of the nontoxic prodrug. The gene product (enzyme) converts the prodrug to a cytotoxin, thereby leading to death of the cancer cell. Molecular modeling of the active site of enzymes and their variants has provided further insights on how the enzyme might be altered to improve prodrug activation and therefore enhance tumor ablation for a safer and more effective cancer cure. Key words: suicide gene therapy, molecular evolution, thymidine kinase, nucleotide metabolizing enzymes.
Teaching Expertise: I teach in two modular/team taught courses for the PharD students. In PharS553 I lecture on anti-neoplastic agents and in the second I teach pharmaceutical biotechnology (PharS554).