Abstract
Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.
Highlights
Protozoan parasites belonging to the Trypanosoma and Leishmania species are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT, known as sleeping sickness), Chagas disease, and different forms of leishmaniasis [1,2]
We recently reported the experimental evidence of cycloguanil (CYC), a known inhibitor of Plasmodial and Trypanosomal dihydrofolate reductase (DHFR)-TS enzymes, as an inhibitor of TbPTR1 [20]
DHFR-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) enzymes play a key role in the production of reduced folates, substances fundamental for the biosynthesis of nucleic acids and proteins
Summary
Protozoan parasites belonging to the Trypanosoma and Leishmania species are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT, known as sleeping sickness), Chagas disease, and different forms of leishmaniasis [1,2]. HAT and Chagas disease are caused by Trypanosoma brucei (T. brucei or Tb) and Trypanosoma cruzi (T. cruzi) infection, respectively, while. Pharmaceuticals 2021, 14, 636 important steps forward in the treatment of HAT have been made by the introduction of the combination therapy eflornithine–nifurtimox and of fexinidazole, the first oral drug against this disease [6,7,8,9]. Despite the efforts to control HAT, drug resistance issues may still occur—a problem further exacerbated by the exitance of animal reservoirs of these diseases [10,11,12]. The development of new drugs effective against protozoan parasites is still an urgent need
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