Targeting atypical trypanosomatid DNA topoisomerase I

Abstract

Tropical diseases produced by kinetoplastid protozoa are among humanity's costliest banes, owing to high mortality and the economic burden resulting from morbidity. Drug resistant strains of parasites, together with insecticide-resistant vectors, are contributing to their increased prevalence in the developing world. Their extension now threatens industrialized countries because of opportunistic infections in immuno-compromised individuals. Current chemotherapy is expensive, has undesirable side effects and, in many patients, is only marginally effective. Based on the clinical success of camptothecin derivatives as anticancer agents, DNA topoisomerases have been identified as targets for drug development. The substantial differences in homology between trypanosome and leishmania DNA topoisomerase IB compared with the human form provides a new lead in the study of the structural determinants that can be targeted.