General Research InterestNucleosides for anticancer, antiviral, and antibiotic therapies.
Research DescriptionNucleoside antimetabolites such as gemcitabine, cytarabine, cladribine, fludarabine, clofarabine, acyclovir, ganciclovir, brivudine, zidovudine, stavudine, and emtricitabine are prodrugs that are widely used as anticancer agents or antiviral agents and their importance continues to increase. These antimetabolites utilize nucleoside salvage pathways for their transformation into active nucleoside triphosphates. Irrespective of the final intracellular targets of the triphosphates, which primarily are human or viral DNA and their respective polymerases or reverse transcriptases, the rate-limiting key activation step of the prodrugs is usually the initial conversion of the nucleoside to the corresponding monophosphate by phosphorylating enzymes, often deoxynucleoside kinases. Thymidine kinase (TK) is one of these deoxynucleoside kinases. Most eukaryotes and prokaryotes and many DNA viruses code for proteins with thymidine kinase activity. However, among all approved nucleoside antimetabolites only the HIV prodrugs zidovudine and stavudine are activated by human thymidine kinase 1 (hTK1). This is probably due to the fact that TKs have the most stringent substrate specificity among all nucleoside kinases and that crystal structures for drug design have only become available very recently. Dr. Tjarks’ research activities focus on the in silico design, synthesis, and biological evaluation of inhibitors and substrates of TKs from e.g. Bacillus anthracis and Epstein-Barr virus as well as from hTK1 for antibiotic, antiviral, and anticancer therapies.
Transinstitutional WorkStaffan Eriksson, M.D. , Ph.D., Swedish University of Agricultural Sciences, evaluation of boronated nucleosides for boron neutron capture therapy.
Rolf F. Barth, M.D., OSU Department of Pathology, evaluation of boronated nucleosides for boron neutron capture therapy.