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Mini review on tricyclic compounds as an inhibitor of trypanothione reductase.

Kumar S, Ali MR, Bawa S - J Pharm Bioallied Sci (2014)

Bottom Line: Trypanosomiasis and leishmaniasis are two most ruinous parasitic infectious diseases caused by Trypanosoma and Leishmania species.The disease affects millions of people all over the world and associated with high morbidity and mortality rates.In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India.

ABSTRACT
Trypanosomiasis and leishmaniasis are two most ruinous parasitic infectious diseases caused by Trypanosoma and Leishmania species. The disease affects millions of people all over the world and associated with high morbidity and mortality rates. The review discuss briefly on current treatment of these parasitic diseases and trypanothione reductase (TryR) as potential targets for rational drug design. The enzyme trypanothione reductase (TryR) has been identified as unique among these parasites and has been proposed to be an effective target against for developing new drugs. The researchers have selected this enzyme as target is due to its substrate specificity in contrast to human analogous glutathione reductase and its absence from the host cell which makes this enzyme an ideal target for drug discovery. In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed.

No MeSH data available.


Related in: MedlinePlus

(a) Structure of Trypanothione and glutathione and their reduced form. (b) Mechanism of redox recycling of T[S]2 to T[SH]2 and GSSG to GSH in parasite and host cell respectively
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Figure 2: (a) Structure of Trypanothione and glutathione and their reduced form. (b) Mechanism of redox recycling of T[S]2 to T[SH]2 and GSSG to GSH in parasite and host cell respectively

Mentions: As potential drug target in trypanosomes and Leishmania, TryR has been identified through the discovery of a fundamental difference between the redox defense system of the trypanosomal/leishmanial parasite and the infected host. The mammalian redox defense system is based on glutathione (l-g-glutamyl-l-cysteinylglycine) and glutathione disulfide reductase (glutathione reductase (GR); EC 1.6.4.2), this system is replaced in trypanosomatids by an analogous system based on trypanothione (N, N-bis [glutathionyl] spermidine) and trypanothione disulfide reductase (TryR; EC 1.6.4.8). The structures of the disulfide substrates for TryR and GR are illustrated in Figure 2. TryR is a nicotinamide adenine dinucleotide phosphate-oxidase-dependent flavoprotein oxidoreductase which maintains an intracellular reducing environment by the recycling of trypanothione disulfide T[S]2 to its dithiol T[SH]2 form. Trypanothione is oxidized back to T[S]2 following reaction with potentially damaging radicals and oxidants generated by aerobic metabolism and by host macrophages. By maintaining a high intracellular ratio of T[SH]2 the TryR redox cycle is a primary line of defense for these parasites against respiratory burst responses from the mammalian host. The trypanothione system is necessary for protozoan survival because the dithiol trypanothione is required for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides and the sequestration/export of thiol conjugates. Moreover, the majority of peroxidases that eliminate the reactive oxygen species generated in the aerobic metabolism are trypanothione dependent. Disabling the function of TryR in Leishmania and T. brucei has been shown to markedly increase the parasites’ sensitivity to oxidative stress.


Mini review on tricyclic compounds as an inhibitor of trypanothione reductase.

Kumar S, Ali MR, Bawa S - J Pharm Bioallied Sci (2014)

(a) Structure of Trypanothione and glutathione and their reduced form. (b) Mechanism of redox recycling of T[S]2 to T[SH]2 and GSSG to GSH in parasite and host cell respectively
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231380&req=5

Figure 2: (a) Structure of Trypanothione and glutathione and their reduced form. (b) Mechanism of redox recycling of T[S]2 to T[SH]2 and GSSG to GSH in parasite and host cell respectively
Mentions: As potential drug target in trypanosomes and Leishmania, TryR has been identified through the discovery of a fundamental difference between the redox defense system of the trypanosomal/leishmanial parasite and the infected host. The mammalian redox defense system is based on glutathione (l-g-glutamyl-l-cysteinylglycine) and glutathione disulfide reductase (glutathione reductase (GR); EC 1.6.4.2), this system is replaced in trypanosomatids by an analogous system based on trypanothione (N, N-bis [glutathionyl] spermidine) and trypanothione disulfide reductase (TryR; EC 1.6.4.8). The structures of the disulfide substrates for TryR and GR are illustrated in Figure 2. TryR is a nicotinamide adenine dinucleotide phosphate-oxidase-dependent flavoprotein oxidoreductase which maintains an intracellular reducing environment by the recycling of trypanothione disulfide T[S]2 to its dithiol T[SH]2 form. Trypanothione is oxidized back to T[S]2 following reaction with potentially damaging radicals and oxidants generated by aerobic metabolism and by host macrophages. By maintaining a high intracellular ratio of T[SH]2 the TryR redox cycle is a primary line of defense for these parasites against respiratory burst responses from the mammalian host. The trypanothione system is necessary for protozoan survival because the dithiol trypanothione is required for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides and the sequestration/export of thiol conjugates. Moreover, the majority of peroxidases that eliminate the reactive oxygen species generated in the aerobic metabolism are trypanothione dependent. Disabling the function of TryR in Leishmania and T. brucei has been shown to markedly increase the parasites’ sensitivity to oxidative stress.

Bottom Line: Trypanosomiasis and leishmaniasis are two most ruinous parasitic infectious diseases caused by Trypanosoma and Leishmania species.The disease affects millions of people all over the world and associated with high morbidity and mortality rates.In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India.

ABSTRACT
Trypanosomiasis and leishmaniasis are two most ruinous parasitic infectious diseases caused by Trypanosoma and Leishmania species. The disease affects millions of people all over the world and associated with high morbidity and mortality rates. The review discuss briefly on current treatment of these parasitic diseases and trypanothione reductase (TryR) as potential targets for rational drug design. The enzyme trypanothione reductase (TryR) has been identified as unique among these parasites and has been proposed to be an effective target against for developing new drugs. The researchers have selected this enzyme as target is due to its substrate specificity in contrast to human analogous glutathione reductase and its absence from the host cell which makes this enzyme an ideal target for drug discovery. In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed.

No MeSH data available.


Related in: MedlinePlus