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Suramin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Suramin is a large molecule and is highly biologically active. The mechanism of action responsible for its trypanocidal action is not well understood. The drug has complex cellular pharmacology, possibly explaining the diverse range of biologic activity and toxicities observed. Suramin inhibits a diverse range of biologic enzymes of both mammalian and protozoan origin. These include dihydrofolate reductase, thymidine kinase, acid phosphatase, acid pyrophosphatase, phospholipase A1, and glycolytic enzymes (Docampo and Moreno, 2003; Nok, 2003). The target trypanosomal enzymes are located in structures including the plasma membrane, flagellar pocket membrane, and the digestive apparatus such as the lysosome (Voogd et al., 1993). Glucose is the sole energy source for the trypanosome, and complex inhibition of glycolytic enzymes may occur in the cytoplasm, in the mitochondrion, in an organelle called the glycosome, or by inhibiting their entry into the glycosome (Harder et al., 2001; Bouteille et al., 2003; Docampo and Moreno, 2003). It has been known for many years that the trypanosomicidal effect of suramin is relatively slow (Hawking and Sen, 1960). More recent rat studies have shown that even at the highest tolerated dose of suramin, trypanosomal growth continues exponentially in the bloodstream for at least 6 hours (Fairlamb and Bowman, 1980). Suramin inhibits the activity of many enzymes that probably have no relation to its antiparasitic effect, including hyaluronidase, urease, hexokinase, fumarase, and trypsin (Pepin and Milord, 1994).
Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Itzhel García-Torres, Ignacio De la Mora-De la Mora, Gabriel López-Velázquez, Nallely Cabrera, Luis Antonio Flores-López, Ingeborg Becker, Juliana Herrera-López, Roberto Hernández, Ruy Pérez-Montfort, Sergio Enríquez-Flores
On the other hand, trypanosomes can undergo abrupt changes such as the passage from one host to another, and even very adverse conditions in pharmacological treatments. Besides, it has been shown that their glycosomes can be renewed through a mechanism called pexophagy, which can involve the generation of new organelles together with the protein composition that characterises them86. For this reason, we evaluated the protein expression of cellular TIM from Rbz-treated and untreated epimastigotes by western blot. Our data allow us to demonstrate that the enzyme maintained normal protein levels and was even slightly up-regulated when the parasite was exposed to the drug (Supplementary Figure S3). Currently, there is no clear evidence of how the protein content of the glycosome is altered (especially the glycolytic enzymes) under conditions of pharmacological treatment. However, due to the stress generated under such conditions, it is suggestive that changes in autophagy occur. For example, one study reported in 2016, in which T. cruzi was exposed to the compound β-lapachone, led to the inhibition of the glycosomal enzymes glycerol kinase and glyceraldehyde-3-phosphate dehydrogenase, as well as autophagy and subsequent cell death87, while in another study, it was demonstrated that in tumour cells treated with the PPI pantoprazole, autophagy was inhibited, which led to decreased cell viability88.
Drugs and nanoformulations for the management of Leishmania infection: a patent and literature review (2015-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Mariana Verdan, Igor Taveira, Flávia Lima, Fernanda Abreu, Dirlei Nico
Polyamines play a fundamental role in cell growth and differentiation. Arginine is an amino acid necessary for Leishmania and host metabolism [76]. Arginase is an enzyme responsible for the cleavage of arginine, producing ornithine and urea. In Leishmania, arginase is one of the relevant enzymes in the polyamine biosynthesis pathway, which is responsible for converting arginine into ornithine [77]. In the Leishmania glycosome, arginase is also involved in trypanothione biosynthesis. Da Silva and colleagues demonstrated fundamental arginase activity in L. amazonensis, confirming arginase as an essential molecular target [78]. This study showed that Leishmania mutants for arginase decreased the power of infection in vitro. By the way, any other critical metabolic marks are under investigation. We will not extend our discussion on this issue so as not to deviate from the topic.