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New Chemical Scaffolds to Selectively Target the Trypanothione Metabolism
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
The enzymes of the trypanothione pathway are not present in human host and are essential for the parasite survival during the infection and for these reasons represent the most promising targets against the diseases caused by trypanosomatids. The structure-function relationships of trypanothione reductase of L. infantum, T. cruzi and T. brucei have been deeply studied and new scaffolds able to inhibit TR have been identified. However, at least 90% TR inactivation needs to be obtained by inhibitor compounds to kill the parasite avoiding the interference of the reduced trypanothione accumulation. Thus, to find new lead compounds targeting TR is quite difficult since effective molecules should have submicromolar inhibition activity as well as show very good selectivity over GR.
Antimonial Agents
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
Aquaglyceroporins (AQPs) are known to transport trivalent metalloids. Aquaglyceroporin 1 (AQP1) has been identified in Leishmania and has been shown to mediate uptake of Sb3+ into the parasite (Gourbal et al., 2004). Once inside the parasite, the primary target is believed to be a specific thiol redox pathway. Trypanothione synthetase and trypanothione reductase are components of thiol pathway metabolism in Leishmania, a pathway common to all parasites of the Trypanosomatidae family but absent in the mammalian host (Baiocco et al., 2009). Trypanothione reductase maintains the main thiols in Leishmania parasite, especially trypanothione, in a reduced state. Trypanothione, possibly in conjunction with thiol-dependent reductase-1, promotes reduction of Sb5+ to Sb3+ (Denton et al., 2004). Trivalent antimony then binds with high affinity to the active site of TR, profoundly inhibiting the thiol reduction potential of the cell (Baiocco et al., 2009). This exposes the parasite to oxidative stress by the reactive oxidative species produced by the host macrophage and facilitates killing of the parasite (Baiocco et al., 2009). A separate target of Sb3+ may be zinc finger proteins involved in DNA repair, leading to DNA fragmentation and ultimately apoptosis (Frezard et al., 2009).
Emerging compounds and therapeutic strategies to treat infections from Trypanosoma brucei: an overhaul of the last 5-years patents
Published in Expert Opinion on Therapeutic Patents, 2023
Francesco Melfi, Simone Carradori, Cristina Campestre, Entela Haloci, Alessandra Ammazzalorso, Rossella Grande, Ilaria D’Agostino
T. cruzi has a unique metabolic pathway based on the trypanothione-based redox system, capable of modulating the redox balance. Trypanothione, being the trypanosomatid-specific form of mammalian glutathione, is responsible for detoxification and accomplishing survival processes and is synthesized by Trypanothione Synthetase. Indeed, trypanothione reductase (TR) is the flavoenzyme that catalyzes the reduction of the antioxidant dithiol trypanothione, protecting trypanosomatids from the oxidative stress generated by host cell defense systems. This represents a highly effective target for the design of new active and selective compounds, because it is not present in the host [93]. The production of this compound relies on the polyamine biosynthetic pathway essential for T. brucei growth and division [94,95]. If the polyamine synthesis or the TR activity is blocked (especially by small molecules or peptidomimetic compounds), the T. brucei parasites suffer from harmful susceptibility to oxidative stress and limited virulence.
Mechanistic and biological characterisation of novel N 5-substituted paullones targeting the biosynthesis of trypanothione in Leishmania
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Andrea Medeiros, Diego Benítez, Ricarda S. Korn, Vinicius C. Ferreira, Exequiel Barrera, Federico Carrión, Otto Pritsch, Sergio Pantano, Conrad Kunick, Camila I. de Oliveira, Oliver C. F. Orban, Marcelo A. Comini
The biosynthesis of T(SH)2 is achieved in two consecutive steps each involving the ligation of a glutathione (GSH) molecule by its glycine carboxyl group to the free N1 and N8 amine groups of spermidine (SP). Both reactions are catalysed by the C-terminal ligase domain of trypanothione synthetase (TryS; EC 6.3.1.9), at the expense of ATP. The indispensability of TryS for the infective form of Trypanosoma brucei (Tb)8,9, Leishmania infantum (Li)10 and, more recently, Trypanosoma cruzi (Tc)11 has been confirmed by means of reverse genetic or chemical inhibition approaches. The high conservation of the trypanothione system among trypanosomatids2,3 suggests that TryS is essential for this protozoan lineage. The development of TryS inhibitors is rather limited compared to work done on the metabolically-related enzyme trypanothione reductase12. Overall, the TryS inhibitors can be grouped in substrate or transition state analogues13,14, natural derivatives15,16 and other synthetic compounds17–19 (Figure 1).
Advances in preclinical approaches to Chagas disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Fernando Villalta, Girish Rachakonda
The trypanothione system is central for any thiol regeneration and trypanothione reductase has been shown to be an essential enzyme in trypanosomatids. The absence of this pathway from the mammalian host and the sensitivity of trypanosomatids toward oxidative stress render the enzymes of the trypanothione metabolism attractive target molecules for the rational development of new drugs against African sleeping sickness, Chagas disease and the different forms of leishmaniasis [79].