Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff‐Targets bei Trypanosomiasis und Malaria

Abstract

Parasitäre Erkrankungen wie Schlafkrankheit, Chagas‐Krankheit oder Malaria gehören zu den Hauptursachen weltweiter Armut. Dringend benötigt werden antiparasitäre Medikamente, die nicht nur wirksam, sondern für die Betroffenen auch erschwinglich und verfügbar sind. Ein Ansatz bei der Suche nach neuen Wirkstoffen (und der Wiederentdeckung alter) basiert auf dem Einsatz von Enzyminhibitoren, die die antioxidativen Systeme in den Pathogenen blockieren. Für Parasiten sind die antioxidativen Netzwerke essentiell, da sie vom menschlichen Wirt durch starke Oxidantien wie Peroxynitrit, Hypochlorit und Wasserstoffperoxid bekämpft werden. Das pathogeneigene Schutzsystem besteht aus etwa zwanzig Thiol‐ und Dithiolproteinen, die das intrazelluläre Redoxmilieu bei einem Potential von etwa −250 mV puffern. Im Zentrum dieses Redoxgefüges steht bei Trypanosomen und Leishmanien das parasitenspezifische Dithiol Trypanothion (N1,N8‐Bis(glutathionyl)spermidin). Malariaparasiten hingegen besitzen ein konservativeres System, das auf Glutathion und Thioredoxin basiert. Inhibitoren von antioxidativen Enzymen wie der Trypanothionreduktase sind per se parasitizid, darüber hinaus können sie aber auch die Entwicklung von Resistenz gegen andere antiparasitäre Wirkstoffe verzögern.

Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities

“…TR, as the central enzyme of this redox system, has been shown to be essential for parasites, rendering this enzyme a promising target for the development of new antitrypanosomal compounds. [9][10][11] Although the closely related enzymes TR and hGR exhibit approximately 40 % sequence identity, [12] they have a mutually exclusive substrate specificity which is thought to rely on their oppositely charged disulfide substrate binding sites. [13] The significant structural differences between TR und hGR suggest that design of selective inhibitors should be possible.…”

“…[15] Nevertheless, various compounds have been identified as inhibitors of TR over the past two decades. [9,10,16] Under physiological conditions, most of these compounds feature a protonated ammonium or a quaternary nitrogen center, which Trypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease.…”

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine‐Conjugated Diaryl Sulfide Scaffolds

“…High costs and an increasing number of drug-resistant pathogens render the treatment even more difficult. [6][7][8] New and better antiparasitic agents are therefore urgently needed.…”

Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines

“…Various compounds have been discovered over the last decade that moderately inhibit TR. [24] Noticeably, several of them feature a basic or quaternary nitrogen connected through a flexible alkyl chain to a hydrophobic core. One of the prototypes of this inhibitor class are diaryl sulfide-based compounds, first reported by Sergheraert et al [25] and further explored by Douglas et al [26] In order to explore the eligibility of SF 5 as a building block for TR inhibitors and to compare it with the corresponding CF 3 or CA C H T U N G T R E N N U N G (CH 3 ) 3 analogues, we designed and synthesized diarylamine derivatives 1-6, which are structurally related to the known class of diphenyl sulfide inhibitors (Scheme 1).…”

“…[22] New and improved drugs to fight these diseases are urgently needed, as current therapy for all forms of trypanosomiases and leishmaniases is problematic due to the severe adverse effects of the drugs in use, the long duration and high costs of treatment, and an increasing number of drug resistant pathogens. [23,24] In the search for new drugs against trypanosomatid-induced diseases, TR has become an increasingly popular target. Various compounds have been discovered over the last decade that moderately inhibit TR.…”