Targeting DHFR in parasitic protozoa

• Published in: Drug Discovery Today 2005-01, Vol.10 (2), p.121-128
• Main Author: Anderson, Amy C.
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Biological and medical sciences; Clinical Trials as Topic; Cryptosporidiosis; Enzyme inhibitors; Eukaryota - drug effects; Eukaryota - enzymology; Eukaryota - physiology; Folic Acid Antagonists - pharmacology; Folic Acid Antagonists - therapeutic use; General pharmacology; Humans; Malaria; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protozoan Infections - drug therapy; Protozoan Infections - enzymology; Structure-based drug design; Tetrahydrofolate Dehydrogenase - chemistry; Tetrahydrofolate Dehydrogenase - metabolism; Toxoplasmosis
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/S1359-6446(04)03308-2

Dihydrofolate reductase inhibitors are the mainstay in the fight against malaria and toxoplasmosis, but new inhibitors will be needed for resistant strains and for cryptosporidiosis, an emerging infectious disease. Parasitic apicomplexans are responsible for some of the most severe worldwide health problems, including malaria, toxoplasmosis and cryptosporidiosis. These parasites are characterized by a bifunctional enzyme, dihydrofolate reductase-thymidylate synthase (DHFR-TS), which has a crucial role in pyrimidine biosynthesis. Inhibitors of DHFR have been successful in the treatment of toxoplasmosis and malaria. However, there is currently no effective therapy for cryptosporidiosis, and despite early successes against malaria, resistance to DHFR inhibitors in malaria parasites has now become a global problem. Novel DHFR inhibitors, designed using the recently revealed crystal structures of the enzymes from two parasitic protozoa, are in development.