Rational search for natural inhibitors of the trypanosomatid pteridine metabolism

Tropical and subtropical regions of the world are severely affected by millions of disease cases caused by trypanosomatid parasites. For example, human African trypanosomiasis (HAT) and cutaneous leishmaniasis (CL) are caused by Trypanosoma brucei (Tb) and Leishmania major (Lm) [1]. The identification of new drugs is urgently needed since current treatment options cause severe side effects and are frequently hampered by resistance developments of the parasites. Trypanosomatids possess a unique pteridine metabolism with an enzyme system consisting of the bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) and the pteridine reductase 1 (PTR1) which represents a highly interesting drug target [2]. In continuation of our previous work [3], [4], we aim for the identification of new lead structures with a dual inhibitory effect against the respective T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes. To this end, we used in silico methods (pharmacophore-based virtual screening of approx. 5000 natual products followed by multi-step docking procedures) to select candidates with potential inhibitory activity towards the target enzymes. Promising compounds were subsequently tested in vitro through spectrophotometric inhibition assays against recombinant DHFR and PTR1 of both investigated parasites. Out of 50 tested compounds, five were identified as dual inhibitors against the Tb enzymes so far (0.2 µM < IC₅₀ < 83.6 µM). Against the corresponding enzymes of Lm, seven out of 35 tested natural products inhibited both of the enzymes in the micromolar range (4.2 µM < IC₅₀ < 84.5 µM). The elucidation of further dual inhibitors as well as their kinetic mechanism(s) of inhibition are the focus of current studies.

Publication History

Article published online:
12 December 2022

• References

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