Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis

  title={Targeting the polyamine biosynthetic enzymes: a promising approach to therapy of African sleeping sickness, Chagas’ disease, and leishmaniasis},
  author={Olle Heby and Lo Persson and Madhubala Rentala},
  journal={Amino Acids},
Summary.Trypanosomatids depend on spermidine for growth and survival. Consequently, enzymes involved in spermidine synthesis and utilization, i.e. arginase, ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (AdoMetDC), spermidine synthase, trypanothione synthetase (TryS), and trypanothione reductase (TryR), are promising targets for drug development. The ODC inhibitor α-difluoromethylornithine (DFMO) is about to become a first-line drug against human late-stage gambiense… 
Targeting the Polyamine Biosynthetic Pathway in Parasitic Protozoa
Differences in protein turnover rates and polyamine transport, the latter of which could be used for delivery of cytotoxic compounds, are discussed.
A decade of targets and patented drugs for chemotherapy of Chagas disease.
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    Recent patents on anti-infective drug discovery
  • 2011
Advances on antichagasic agents directed to specific parasite targets such as metabolic pathways or specific enzymes, including cysteine proteinase inhibitors and inhibitors capable to block ergosterol biosynthesis, are summarized.
Trypanosoma cruzi targets for new chemotherapeutic approaches
There is an urgent need for better drugs to treat chagasic patients and the state of the art of drug targets against Trypanosoma cruzi is reviewed with emphasis on sterol metabolism, kinetoplast DNA sites, trypanothione reductase, cysteine proteinase, hypoxanthine–guanine phosphoribosyltransferase and glyceraldehyde-3-phosphate dehydrogenase.
Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target
This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, S-adenosylmethionine decarate synthase, and spermidine synthase and emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against Leishmania parasites.
Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities
In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined, including prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism intrypanosomeids.
Structural Insight into DFMO Resistant Ornithine Decarboxylase from Entamoeba histolytica: An Inkling to Adaptive Evolution
The fact that EhODC sequence has conserved PLP binding residues is established, in contrast few substrate binding residues are mutated similar to AZI, which may represent as an evolutionary bridge between active decarboxylase and inactive AZI.
Chapter II Genetic Manipulation of Leishmania Parasites Facilitates the Exploration of the Polyamine Biosynthetic Pathway As a Potential Therapeutic Target
This chapter will summarize how genetic manipulations in Leishmania have advanced the authors' understanding of the polyamine pathway and its role in host-parasite interactions.
Potential Drug Targets in the Pentose Phosphate Pathway of Trypanosomatids.
An overview of the available chemotherapeutic options against infectious diseases and the potential of genetically validated enzymes from the pentose phosphate pathway of trypanosomatids to be explored as potential drug targets are discussed.
Trypanosoma cruzi Coexpressing Ornithine Decarboxylase and Green Fluorescence Proteins as a Tool to Study the Role of Polyamines in Chagas Disease Pathology
This double-transfected T. cruzi parasite, that expresses the green fluorescent protein and a heterologous ornithine decarboxylase (ODC), used itself as a novel selectable marker and showed higher metacyclogenesis capacity than the auxotrophic counterpart, supporting the idea that polyamines are engaged in this process.


Leishmania donovani Polyamine Biosynthetic Enzyme Overproducers as Tools To Investigate the Mode of Action of Cytotoxic Polyamine Analogs
The drug resistance engendered by the amplification of target genes and the overproduction of the encoded protein offers a general strategy for evaluating and developing therapeutic agents that target specific proteins in Leishmania.
Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase.
The results suggest that in these parasites cultivated in the presence of the drug, spermidine might decrease below critical levels needed to maintain trypanothione concentrations or other conditions essential for normal proliferation.
Antileishmanial Effect of 3-Aminooxy-1-Aminopropane Is Due to Polyamine Depletion
It is demonstrated that 3-aminooxy-1-aminopropane (APA), an ODC inhibitor, is a potent inhibitor of L. donovani growth and that its leishmaniacidal effect is due to inhibition of ODC.
In vivo trypanocidal activities of new S-adenosylmethionine decarboxylase inhibitors
One agent, CGP 40215A, a bicyclic analog of MGBG which also resembles the diamidines diminazene (Berenil) and pentamidine, was curative of infections by 19 isolates of Trypanosoma brucei subspecies as well as a TrypanOSoma congolense isolate, indicating that one possible mechanism of its action may be inhibition of polyamine biosynthesis.
Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells.
The capacity of blood (trypomastigote) forms of Trypanosoma cruzi to infect mouse peritoneal macrophages or rat heart myoblasts in vitro was inhibited and the importance of polyamines and polyamine biosynthesis in the following two important functions of T. cruzi: invasion of host cells and intracellular multiplication was indicated.
Genetic analysis of spermidine synthase from Leishmania donovani.
Polyamine biosynthetic enzymes as drug targets in parasitic protozoa.
These enzymes exhibit features that differ significantly between the parasites and the human host so it is conceivable that exploitation of such differences can lead to the design of new inhibitors that will selectively kill the parasites while exerting minimal, or at least tolerable, effects on the parasite-infected patient.
Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase.
Data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.
Thirty years of polyamine-related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors.
One of the lessons that had to be learned from the work on selective enzyme inhibitors was that PA metabolism is a much more difficult target, than has been expected on the basis of the simplicity of the PA structures, and the simple reactions involved in their biosynthesis.
Trypanosoma cruzi has not lost its S-adenosylmethionine decarboxylase: characterization of the gene and the encoded enzyme.
All attempts to identify ornithine decarboxylase in the human pathogen Trypanosoma cruzi have failed. The parasites have instead been assumed to depend on putrescine uptake and S-adenosylmethionine