1. Recent Advancement in the Search of Innovative Antiprotozoal Agents Targeting Trypanothione Metabolism.
- Author
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Saccoliti F, Di Santo R, and Costi R
- Subjects
- Amide Synthases antagonists & inhibitors, Amidohydrolases antagonists & inhibitors, Animals, Chagas Disease drug therapy, Enzyme Inhibitors chemistry, Enzyme Inhibitors therapeutic use, Glutathione metabolism, Humans, Leishmania drug effects, Leishmania enzymology, Leishmaniasis drug therapy, NADH, NADPH Oxidoreductases antagonists & inhibitors, Protozoan Proteins antagonists & inhibitors, Spermidine metabolism, Trypanocidal Agents chemistry, Trypanocidal Agents therapeutic use, Trypanosoma drug effects, Trypanosoma enzymology, Enzyme Inhibitors pharmacology, Glutathione analogs & derivatives, Spermidine analogs & derivatives, Trypanocidal Agents pharmacology
- Abstract
Leishmania and Trypanosoma parasites are responsible for the challenging neglected tropical diseases leishmaniases, Chagas disease, and human African trypanosomiasis, which account for up to 40,000 deaths annually mainly in developing countries. Current chemotherapy relies on drugs with significant limitations in efficacy and safety, prompting the urgent need to explore innovative approaches to improve the drug discovery pipeline. The unique trypanothione-based redox pathway, which is absent in human hosts, is vital for all trypanosomatids and offers valuable opportunities to guide the rational development of specific, broad-spectrum and innovative anti-trypanosomatid agents. Major efforts focused on the key metabolic enzymes trypanothione synthetase-amidase and trypanothione reductase, whose inhibition should affect the entire pathway and, finally, parasite survival. Herein, we will report and comment on the most recent studies in the search for enzyme inhibitors, underlining the promising opportunities that have emerged so far to drive the exploration of future successful therapeutic approaches., (© 2020 Wiley-VCH GmbH.)
- Published
- 2020
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