Short Lecture "In silico and in vitro search for inhibitors of Trypanosoma brucei and Leishmania major pteridine reductase 1 and dihydrofolate reductase"

The closely related protozoan parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) are responsible for the insect-borne tropical diseases sleeping sickness, nagana and cutaneous leishmaniasis. They bear a significant health risk to millions of humans and animals living in tropical to subtropical climates, threatening and debilitating affected populations. Stemming from the parasites’ highly adaptive nature, the regularly occurring resistances to existing medication options require the identification of new drugs. Arising from a shared pteridine-auxotrophy known for Trypanosomatidae, Tb and Lm developed a corresponding enzyme system consisting of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1). Expanding our previous work on this target, a comparative study of the respective T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes was employed to identify new lead structures, especially focusing on natural products with a dual inhibitory effect against PTR1 and DHFR of the respective parasites. Building on our results presented at the preceding conference, our pharmacophore-based in silico screening approach was used to identify further promising compounds for testing against recombinant DHFR and PTR1. The most active dual inhibitor 1 ([Fig. 1]) exhibited an IC₅₀ of 20.1 µM against TbPTR1 and 0.2 µM against TbDHFR as well as 10.2 µM against LmPTR1 and 2.6 µM for LmDHFR. Furthermore, the kinetic mechanism of action was investigated for selected inhibitors, using the data generated from the in silico and in vitro experiments. These results represent an important contribution for the future utilisation of the trypanosomatid pteridine metabolism as drug target.

Fig. 1 Structure of Compound 1

Publication History

Article published online:
16 November 2023