Targeting thymidylate biosynthesis in kinetoplastid and apicomplexan protozoans

Kinetoplastid and apicomplexan parasites include protozoans which are responsible for human diseases, and cause a serious impact on human health and the socioeconomic growth of developing countries. Chemotherapy is the main option to control these pathogenic organisms. The organisms' nuclear metabolism is considered a promising area for the provision of antimicrobial therapeutic targets.

The viability of parasitic protozoa is severely diminished by imparing thymidylate (dTMP) biosynthesis. The absence of enzymatic activities which are specifically involved in the formation of dTMP (e.g. dUTPase, thymidylate synthase, dihydrofolate reductase or thymidine kinase) results in decreased de-oxythymidine triphosphate (dTTP) levels and the so-called thymineless death.

In this process, the ratio of deoxyuridine triphosphate (dUTP) as compared to dTTP in the cellular nucleotide pool has a crucial role. A high dUTP/dTTP ratio leads to uracil misincorporation into DNA, which then leads to the activation of DNA repair pathways, DNA fragmentation and eventually cell death.

For the identification and development of drugs, the essential character of dTMP synthesis has stimulated interest. These agents specifically block the biochemical steps involved in thymine nucleotide formation.

The review covers available literature related to drug discovery of agents targeting thymidylate biosynthesis in kinetoplastid (genera Trypanosoma and Leishmania) and apicomplexan (Plasmodium spp and Toxoplasma gondii) protozoans.The most relevant findings concerning novel inhibitory molecules with anti-parasitic activity against these human pathogens are presented in the review.

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