An overview of chemotherapeutic targets for antimalarial drug discovery

The need for new antimalarials comes from the widespread resistance to thos e in current use. New antimalarial targets are required to allow the discov ery of chemically diverse, effective drugs. The search for such new targets and new drug chemotypes will likely be helped by the advent of functional genomics and structure-based drug design. After validation of the putative targets as those capable of providing effective and safe drugs, targets can be used as the basis for screening compounds in order to identify new lead s, which, in turn, will qualify for lead optimization work. The combined us e of combinatorial chemistry-to generate large numbers of structurally dive rse compounds-and of high throughput screening systems-to speed up the test ing of compounds-hopefully will help to optimize the process. Potential che motherapeutic targets in the malaria parasite can be broadly classified int o three categories: those involved in processes occurring in the digestive vacuole, enzymes involved in macromolecular and metabolite synthesis, and t hose responsible for membrane processes and signalling. The processes occur ring in the digestive vacuole include haemoglobin digestion, redox processe s and free radical formation, and reactions accompanying haem release follo wed by its polymerization into haemozoin. Any enzymes in macromolecular and metabolite synthesis are promising potential targets, some of which have b een established in other microorganisms, although not yet validated for Pla smodium, with very few exceptions (such as dihydrofolate reductase). Protei ns responsible for membrane processes, including trafficking and drug trans port and signalling, are potentially important also to identify compounds t o be used in combination with antimalarial drugs to combat resistance. PHAR MACOL THER. 81(2):91-110, 1999. (C) 1999 Elsevier Science Inc. All rights r eserved.