Abstract
With current drug treatments failing due to toxicity, low efficacy and resistance; leishmaniasis is a major global health challenge that desperately needs new validated drug targets. Inspired by activity of the natural chalcone 2',6'-dihydroxy-4'-methoxychalcone (DMC), the nitro-analogue, 3-nitro-2',4',6'- trimethoxychalcone (NAT22, 1c) was identified as potent broad spectrum antileishmanial drug lead. Structural modification provided an alkyne containing chemical probe that labelled a protein within the parasite that was confirmed as cytosolic tryparedoxin peroxidase (cTXNPx). Crucially, labelling is observed in both promastigote and intramacrophage amastigote life forms, with no evidence of host macrophage toxicity. Incubation of the chalcone in the parasite leads to ROS accumulation and parasite death. Deletion of cTXNPx, by CRISPR-Cas9, dramatically impacts upon the parasite phenotype and reduces the antileishmanial activity of the chalcone analogue. Molecular docking studies with a homology model of in-silico cTXNPx suggest that the chalcone is able to bind in the putative active site hindering access to the crucial cysteine residue. Collectively, this work identifies cTXNPx as an important target for antileishmanial chalcones.
Highlights
The leishmaniases are a complex group of vector-borne diseases caused by protozoan parasites of genus Leishmania
This work opens a new perspective in the search for treatments for leishmaniasis, an important but neglected tropical disease which impacts millions of people worldwide and has a high economic and social impact
S2 Fig. Uncropped SDS-PAGEs corresponding to Fig 3C. SDS-PAGE of all tested conditions stained with comassie blue. Fluorescence image of all tested conditions. (TIF)
Summary
The leishmaniases are a complex group of vector-borne diseases caused by protozoan parasites of genus Leishmania. Clinical manifestations vary according to the parasite species and the host immunological status [4]. These range from the more benign skin ulcers in cutaneous leishmaniasis (CL) to visceral leishmaniasis (VL), which infects the spleen, liver, and bone marrow and it is fatal in more than 95% of untreated cases [4]. With no human vaccine available, treatment relies on chemotherapy and the current pharmacopeia is reliant on a limited number of drugs: pentavalent antimonials, amphotericin B, pentamidine, miltefosine and paramomycin [5]. With approximately 1 million new cases of CL and 90,000 cases of VL each year worldwide, there is a major unmet need to develop new broad-spectrum chemotherapies based on new validated drug targets [7]
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