The World Health Organization estimates that malaria infects over 800 million people, causes serious disease in over 150 million individuals, and claims 1 to 2 million lives a year. It is the most destructive single infectious agent of mankind in the Third World. Furthermore, it is responsible for more human energy loss, debilitation, loss of work capacity, and economic damage than any other human ailment facing the world today. The specific aim of this proposal is to test novel morpholino-type antisense molecules for anti-malarial activity by targeting a critical gene of Plasmodium which encodes the bifunctional enzyme dihydrofolate reductase/thymidine synthase. This enzyme is essential for folate synthesis and salvage in the malarial parasite. The major obstacles to overcome in the development of antisense-type therapeutic agents include: stability to nuclease activity, transport/delivery, binding affinity, target specificity, ease of synthesis, and cost effectiveness. The novel morpholino-type antisense agents overcome all of these potential drawbacks. Based on preliminary information, we believe that these molecules will be readily taken up by Plasmodium falciparum-infected erythrocytes and result in the suppression of parasite growth. Specifically, we intend to develop novel morpholino- type antisense molecules as anti-malarial/anti-parasitic therapeutic agents.