Targeting the trypanosomatidic enzymes pteridine reductase and dihydrofolate reductase.

Drugs currently in use against Leishmania and Trypanosoma infections have limitations in terms of efficacy, safety, duration of the treatment, toxicity and resistance. It therefore is mandatory to identify molecular targets to be specifically inhibited. Folate is an essential cofactor in the biosynthesis of DNA and amino acids. The inhibition of its metabolism leads to the alterations of cell replication and function. Only a few trypanosomatid enzymes of the folate pathway are presently discussed as potential targets, among them the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase (PTR). The identification of a specific enzyme such as PTR1, able to reduce folates other than biopterins, allowed the understanding of the resistance of trypanosomatids against known antifolate drugs. In most cases only the inhibition of both enzymes, DHFR-TS and PTR would fully arrest the pathway’s metabolic function. The proposed combination therapy opens up a novel approach: re-positioning of the well established antifolate strategy for the treatment of trypanosomatid diseases by the discovery of novel antifolates that complement the efficacy profile of known drugs. The present article compiles the existing medicinal chemistry approaches specifically targeting the folate pathway in trypanosomatids, in particular PTR and the DHFR activity of DHFR-TS. It covers the structural biology of the targets, related computational studies, core structures synthesis and biological inhibitor characterization.