Thymidine is a precursor for the manufacture of two anti-AIDS drugs, AZT and d4T. Currently, thymidine is manufactured primarily through a chemical synthesis process. AZT manufacturing cost is very sensitive to thymidine price since the AZT production process is based on a relatively low yield, multiple-step synthesis from thymidine. Reduction on the pnce of thymidine should greatly reduce the cost of AZT treatment for AIDS patients. A fermentation process for the production of thymidine has been developed. The fermentation process has the potential to greatly reduce the cost of manufacturing thymidine. Two key enzymes from phages have been utilized through gene cloning and expression. The joint expression causes cells to excrete significant amounts of thymidine. The production of either enzyme is lethal to the cells. The genes for both enzymes have been modified so that their expression is tightly regulated and is inducible by a temperature shift. One of the phage genes has been stably integrated into the host chromosome. The research will integrate and stabilize the three genes that code for the second enzyme to achieve a fermentation process with a commercial thymidine titer.Awardee's statement of the potential commercial applications of the research: AZT (Retrovir/R) is the main drug treatment used for AIDS patients and the deoxyribonucleoside, thymidine, is its key precursor. This new fermentation process is expected to reduce the full cost of thymidine from its current @ $400/kg to less than $100/kg, leading to a much lower production cost and hopefully price of AZT. A new AIDS drug, d4T, in clinical trials and available to the public under the Parallel Track Program, is also produced from thymidine.National Institute of Allergy and Infectious Diseases (NIAID)
