Perspectives for new drugs against trypanosomiasis and leishmaniasis.
Diseases caused by pathogenic trypanosomatids cause great suffering throughout the developing world. New drugs for these diseases are urgently needed. Recent technological advances have permitted the identification and validation of numerous drug targets in these organisms. However, efforts to develop inhibitors of these targets, that may then be taken forward for development into new drugs, have been comparatively scarce. In this review we discuss the design, synthesis and evaluation of inhibitors of two drug targets in trypanosomatids, 6-phosphogluconate dehydrogenase, the third enzyme of the pentose phosphate pathway, and dihydrofolate reductase, a key enzyme involved in DNA synthesis. Enzyme inhibitors can only be useful as drugs if they can enter cells and bind to their targets. Therefore we also discuss approaches to designing molecules that can specifically cross the plasma membrane of African trypanosomes via unusual nutrient transporters.
Barrett
Michael P
MP
University of Glasgow, Institute of Biomedical and Life Sciences, Division of Infection & Immunity, The Joseph Black Building, Glasgow, G12 8QQ, U.K. m.barrett@bio.gla.ac.uk
Gilbert
Ian H
IH
D000818:Animals; D016503:Drug Delivery Systems / Q000639:trends; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007896:Leishmaniasis / Q000188:drug therapy*; D010271:Parasites / Q000201:enzymology; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D014352:Trypanosomiasis / Q000188:drug therapy*
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D010734:Phosphogluconate Dehydrogenase; D013762:Tetrahydrofolate Dehydrogenase