Design, Synthesis, and Biological Evaluation of Phosphinopeptides against <i>Trypanosoma cruzi</i> Targeting Trypanothione Biosynthesis

Ravaschino, Esteban L.; Docampo, Roberto; Rodríguez, Juan B.

doi:10.1021/jm050922i

Cited by 46 publications

(19 citation statements)

References 56 publications

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“…Such data are consistent with studies on T. cruzi where TSA inhibitors displayed potent trypanocidal effects (31). These observations strongly suggest that the enzyme is a potential drug target.…”

supporting

confidence: 90%

Leishmania Trypanothione Synthetase-Amidase Structure Reveals a Basis for Regulation of Conflicting Synthetic and Hydrolytic Activities

Fyfe

Oza

Fairlamb

et al. 2008

Journal of Biological Chemistry

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The bifunctional trypanothione synthetase-amidase catalyzes biosynthesis and hydrolysis of the glutathione-spermidine adduct trypanothione, the principal intracellular thiolredox metabolite in parasitic trypanosomatids. These parasites are unique with regard to their reliance on trypanothione to determine intracellular thiol-redox balance in defense against oxidative and chemical stress and to regulate polyamine levels. Enzymes involved in trypanothione biosynthesis provide essential biological activities, and those absent from humans or for which orthologues are sufficiently distinct are attractive targets to underpin anti-parasitic drug discovery. The structure of Leishmania major trypanothione synthetase-amidase, determined in three crystal forms, reveals two catalytic domains. The N-terminal domain, a cysteine, histidine-dependent amidohydrolase/peptidase amidase, is a papain-like cysteine protease, and the C-terminal synthetase domain displays an ATP-grasp family fold common to C:N ligases. Modeling of substrates into each active site provides insight into the specificity and reactivity of this unusual enzyme, which is able to catalyze four reactions. The domain orientation is distinct from that observed in a related bacterial glutathionylspermidine synthetase. In trypanothione synthetase-amidase, the interactions formed by the C terminus, binding in and restricting access to the amidase active site, suggest that the balance of ligation and hydrolytic activity is directly influenced by the alignment of the domains with respect to each other and implicate conformational changes with amidase activity. The potential inhibitory role of the C terminus provides a mechanism to control relative levels of the critical metabolites, trypanothione, glutathionylspermidine, and spermidine in Leishmania.

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supporting

confidence: 90%

Leishmania Trypanothione Synthetase-Amidase Structure Reveals a Basis for Regulation of Conflicting Synthetic and Hydrolytic Activities

Fyfe

Oza

Fairlamb

et al. 2008

Journal of Biological Chemistry

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“…The key step of the synthesis is coupling phosphinates 130 with dipeptide 131 in the presence of N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Protecting group cleavage by catalytic hydrogenation afforded the desired pseudopeptides of which the compounds 133d and 133e were found to be potent inhibitors against Trypanosoma cruzi [262].…”

Section: Peptides Containing P-terminal Aminophosphonate or Aminophosmentioning

confidence: 99%

Chemistry of Aminophosphonic Acids and Phosphonopeptides

Kukhar

Romanenko

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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Aminophosphonic (and aminophosphinic) acids occupy a prominent position in the understanding of bioprocesses in living organisms and in the construction of new bioregulators -pharmaceuticals and agrochemicals. The so-called phosphorus analogs of the amino acids, aminophosphonic and aminophosphinic acids, are amino acid mimetics in which the carboxylic group is substituted by a phosphonic acid residue P(O)(OH) 2 or phosphinic acid group P(O)(OH)R. The replacement of the carboxylic group by a phosphonic or related moiety results in a number of important consequences: the central atom of a phosphonic acid function consists of an additional substituent that has a tetrahedral configuration in contrast to the planar carbonyl atom of carboxylic group. There are also significant differences in the acidity and steric bulk of these residues. The tetrahedral configuration of the pentavalent phosphorus atom mimics the transition state of the peptide bond cleavage reaction in some enzyme-substrate interactions that is used in the synthesis of new inhibitors. The hydrolytic stability of CÀP bonds is often used in order to prepare stable analogs of bioactive phosphates OÀP(O)(OH) 2 . In addition, aminophosphonic acids and their derivatives are important as metal-complexing agents, which have diagnostic and therapeutic applications, and as industrial chemicals in water treatment, metal extraction, or pollution control.Synthesis, and the chemical, physical, and biological properties of aminophosphonic acids and some directions for their practical application are presented in a number of reviews and book chapters. The most comprehensive account of the chemistry and biology of aminophosphonates and aminophosphinate which covers literature up to 2000 is presented in Kukhar and Hudson ([1] and references therein). Readers are referred to this reference for more detailed information concerning specific aspects of the chemistry and biological activity of aminophosphonic acid derivatives. The purpose of this chapter is to give an updated report on aminophosphonic acids as analogs of amino acids. Numerous heterocyclic compounds that contain both phosphonic and amino groups will not be covered in this report.

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“…derivatives of glutathione like L-γ-Glu-L-Leu-Gly tripeptide of general formula 57 were synthesized and tested against T. cruzi epimastigotes by Ravaschino et al but no inhibitory activity was detected at a concentrations up to 20 µg/ml [192] (Fig. 17).…”

Section: Growth Inhibition Assaysmentioning

confidence: 99%

Progresses in the Field of Drug Design to Combat Tropical Protozoan Parasitic Diseases

Liñares

Ravaschino²,

Rodríguez

2006

CMC

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The progresses made in the field of drug design to combat tropical protozoan parasitic diseases, such as Chagas' disease, leishmaniasis, and sleeping sickness are discussed. This article is focused on different approaches based on unique aspects of parasites biochemistry and physiology, selecting the more promising molecular targets for drug design. In spite of the enormous amount of work on the above features, the chemotherapy for all of these diseases remains unsolved. It is based on old and fairly not specific drugs associated, in several cases, with long-term treatments and severe side effects. Drug resistance and different strains susceptibility are further drawbacks of the existing chemotherapy. In this review article, a thorough analysis of selected molecular targets, mainly those that are significantly different compared with the mammalian host or, even, are not present in mammals would be described in terms of their potencial usefulness for drug design. Therefore, this article covers rational approaches to the chemotherapeutic control of these parasitic infections, such as the progresses in the search for novel metabolic pathways in parasites that may be essential for parasites survival but with no counterpart in the host. Ergosterol biosynthesis is a very interesting example. There are many enzymes involved in this biosynthetic pathway such us squalene synthase, farnesylpyrophosphate synthase, and other enzymes that are able to deplete endogenous sterols will be treated in this article. The enzymes involved in trypanothione biosynthesis, glutathionyl spermidine synthetase and trypanothione synthetase do not have an equivalent in mammals, and therefore it can be predicted low toxicity for compounds that are able to produce highly selective inhibition. Trypanothione reductase (TR), glyceraldehyde-3-phosphate dehydrogenase, dihydrofolate reductase, prenyltransferases, ornithine decarboxylase, etc, will be thoroughly analyzed. The design of specific inhibitors of such metabolic activities as possible means of controlling the parasites without damaging the hosts will be presented. The recent advances in the biochemistry of pathogenic parasites including the discovery of novel organelles will be discussed.

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Design, Synthesis, and Biological Evaluation of Phosphinopeptides against Trypanosoma cruzi Targeting Trypanothione Biosynthesis

Cited by 46 publications

References 56 publications

Leishmania Trypanothione Synthetase-Amidase Structure Reveals a Basis for Regulation of Conflicting Synthetic and Hydrolytic Activities

Leishmania Trypanothione Synthetase-Amidase Structure Reveals a Basis for Regulation of Conflicting Synthetic and Hydrolytic Activities

Chemistry of Aminophosphonic Acids and Phosphonopeptides

Progresses in the Field of Drug Design to Combat Tropical Protozoan Parasitic Diseases

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