Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

Field, Mark C.; Horn, David; Fairlamb, Alan H.; Ferguson, Michael A. J.; Gray, David W.; Read, Kevin D.; Rycker, Manu De; Torrie, Leah S.; Wyatt, Paul G.; Wyllie, Susan; Gilbert, Ian H.

doi:10.1038/nrmicro.2016.193

“…The trypanosomatid lineage diverged early in eukaryote phylogeny and evolved peculiar or unusual biological features (3). Investigations of unusual cellular and molecular mechanisms that are conserved among trypanosomatid species can provide new drug targets or vaccine strategies (2).…”

Section: Introductionmentioning

confidence: 99%

Fluorescence‐based assay for accurate measurement of transcriptional activity in trypanosomatid parasites

Hiraiwa

¹

,

Aguiar

²

,

Ávila

³

2018

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Trypanosomatid parasites are causative agents of neglected human diseases. Their lineage diverged early from the common eukaryotic ancestor, and they evolved singular mechanisms of gene expression that are crucial for their survival. Studies on unusual and essential molecular pathways lead to new drug targets. In this respect, assays to analyze transcriptional activity will provide useful information to identify essential and specific factors. However, the current methods are laborious and do not provide global and accurate measures. For this purpose, a previously reported radiolabeling in vitro nascent mRNA methodology was used to establish an alternative fluorescent-based assay that is able to precisely quantify nascent mRNA using both flow cytometry and a high-content image system. The method allowed accurate and global measurements in Trypanosoma brucei, a representative species of trypanosomatid parasites. We obtained data demonstrating that approximately 70% of parasites from a population under normal growth conditions displayed mRNA transcriptional activity, whilst the treatment with α-amanitin (75 µg/ml) inhibited the polymerase II activity. The adaptation of the method also allowed the analyses of the transcriptional activity during the cell cycle. Therefore, the methodology described herein contributes to obtaining precise measurements of transcriptional rates using multiparametric analysis. This alternative method can facilitate investigations of genetic and biochemical processes in trypanosome parasites and consequently provide additional information related to new treatment or prophylaxis strategies involving these important human parasites.

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“…[1] Der vorwiegend über Raubwanzen übertragene Erreger Trypanosoma cruzi (T. cruzi)v erursacht die Chagas-Krankheit, die laut der Weltgesundheitsorganisation (WHO) circa 6-7 Millionen Menschen weltweit betrifft, vor allem in Mittel-und Südamerika. In Afrika verursacht Trypanosoma brucei (T. brucei)n ach Übertragung durch infizierte Tsetse-Fliegen die Schlafkrankheit bei Menschen und Nutztieren.…”

unclassified

“…In Afrika verursacht Trypanosoma brucei (T. brucei)n ach Übertragung durch infizierte Tsetse-Fliegen die Schlafkrankheit bei Menschen und Nutztieren. [1] Die molekularen Mechanismen der meisten antitrypanosomalen Medikamente basieren auf der gleichzeitigen Beeinflussung mehrerer Zielproteine. [1] Beide Krankheiten kçnnen ohne Behandlung tçdlich verlaufen.…”

unclassified

“…[1] Der vorwiegend über Raubwanzen übertragene Erreger Trypanosoma cruzi (T. cruzi)v erursacht die Chagas-Krankheit, die laut der Weltgesundheitsorganisation (WHO) circa 6-7 Millionen Menschen weltweit betrifft, vor allem in Mittel-und Südamerika. [1] Das überwiegende Auftreten von Tr ypanosomien in unterentwickelten Länder,d as Fehlen eines Impfstoffs bzw.e iner effektiven medikamentçsen Behandlung hat die WHO dazu veranlasst, die Schlafkrankheit und die Chagas-Krankheit als vernachlässigte Tr openkrankheiten einzustufen. Die gegenwärtigen Behandlungsmçglichkeiten (Pentamidin, Suramin, Eflornithin, Nifurtimox, Melarsoprol und Benznidazol) sind aufgrund dosisbegrenzender Nebenwirkungen und zunehmender Therapieresistenz nicht zufriedenstellend.…”

unclassified

“…[1] Beide Krankheiten kçnnen ohne Behandlung tçdlich verlaufen. [1] Die Blutkreislaufformen von Tr ypanosomen sind von der Glykolyse,also der Umwandlung von Glukose in Pyruvat und Adenosintriphosphat (ATP), abhängig.D ie ersten Schritte des trypanosomalen Glukosestoffwechsels erfolgen in subzellulären Kompartimenten, die als Glykosomen bezeichnet werden. [1] Die molekularen Mechanismen der meisten antitrypanosomalen Medikamente basieren auf der gleichzeitigen Beeinflussung mehrerer Zielproteine.…”

unclassified

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Die Hemmung von Protein‐Protein‐Wechselwirkungen: neue Ansätze zur Entwicklung von Wirkstoffen gegen Tropenkrankheiten

Berg

¹

2017

Angewandte Chemie

0

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Leishmaniases

Chang¹

2021

Encyclopedia of Life Sciences

1

0

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Leishmaniases are neglected tropical diseases. The causative agents, Leishmania spp., are transmitted by the blood‐sucking female sand flies. The diseases are largely a zoonosis of canines, rodents and edentates. Humans are accidental dead‐end hosts, except in some places where human–human transmission is indicated by the absence of animal reservoirs. The diseases are present in >100 countries, mainly in tropical and subtropical areas, putting one billion world population at risk with an annual caseload of ∼one million and death in the tens of thousands. Leishmaniases are marked by a spectrum of clinical manifestations, ranging from self‐healing cutaneous lesions to facial mucocutaneous disfiguration to visceralisation with fatal consequence. Clinical managements of visceral leishmaniases rely on several toxic drugs with decreasing efficacy due to the development of drug resistance. Intraphagolysosomal parasitism of macrophages by these parasites is a key feature for considering molecular mechanisms of their virulence relevant to developing effective drugs and vaccines needed. Key Concepts The trypanosomatid protozoa in the genus of Leishmania cause leishmaniases. The diseases are neglected, but very widespread mainly in tropical and subtropical countries. The parasites live briefly in blood‐sucking sand flies and develop into infective promastigotes in the gut lumen. Infected sand flies transmit the parasites among animals, e.g. canines, rodents and edentates. Humans acquire leishmaniases from sand fly bites as a zoonosis with infected wild and domestic animals as the reservoirs. Human leishmaniasis is referred to as anthroponotic where reservoir animals have not been identified. The parasites live in the acidic endosomes/lysosomes of macrophages as amastigotes in the mammalian hosts. There are cutaneous, mucocutaneous and visceral leishmaniases. The spectrum of clinical manifestations results from immunopathology of different host‐parasite interactions. Life‐long immunity to leishmaniases often develops in patients cured of these diseases. Chemotherapy of leishmaniases relies on toxic drugs and loses its effectiveness to drug‐resistance. Visceral leishmaniasis has been brought under control in some endemic countries. Control programs include diagnosis of patients for treatments, surveillance of reservoirs and vectors for elimination. Lack of incentives for drug and vaccine development accounts for the persistence of leishmaniases.

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Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need

Cited by 353 publications

References 166 publications

Fluorescence‐based assay for accurate measurement of transcriptional activity in trypanosomatid parasites

Fluorescence‐based assay for accurate measurement of transcriptional activity in trypanosomatid parasites

Die Hemmung von Protein‐Protein‐Wechselwirkungen: neue Ansätze zur Entwicklung von Wirkstoffen gegen Tropenkrankheiten

Leishmaniases

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