Target-Based Drug Discovery for Malaria, Leishmaniasis, and Trypanosomiasis

Karl   A.   Werbovetz

doi:10.2174/0929867003374615

Abstract

Advances in combinatorial chemistry, high-throughput screening, and molecular modeling have revolutionized the process of drug discovery in the pharmaceutical industry. Drug discovery efforts for the primary protozoal parasitic diseases of the developing world, malaria, leishmaniasis, and trypanosomiasis, have also begun to employ these tech-niques. Drug targets in these parasites, exemplified by cysteine proteases and trypanothione reductase, have been purified and used for inhibitor screening. Through this work, small molecules have been identified that inhibit both parasite proteins and the growth of the organisms. This review describes advances that have been made in examining the effects of small molecules on potential parasitic drug targets determined by biochemical and computer-based screening, and also details the activity of such compounds on parasites in vitro and in vivo. Based on these results, it is apparent that modern drug discovery techniques hold promise for the identification of antiparasitic drug candidates.

Keywords: malaria, leishmaniasis, combinatorial chemistry, high throughput screening, molecular modeling, parasitic diseases, rhodesiense, plasmodium, anopheles, leishmania, trypanosoma brucei, trypansoma cruzi, antileishmanial, antitrypanosomal, trypanothione reductase, polyamine derivatives, proteases, cruzain, serine oligopeptidase, trypanopain Tb, transporters, trypanosome transporters, nucleic acid synthesis, leishmania nucleoside transporters, cruzi diamine transporter, hexose transporter, glycolytic enzyme, phosphoribosyltransferases, tubulin, malarial proteases, falcipain inhibitors, plasmepsin inhibitors, lactate dehydrogenase