In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 15, No. 11 ( 2021-11-15), p. e0009951-
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.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0009951
DOI:
10.1371/journal.pntd.0009951.g001
DOI:
10.1371/journal.pntd.0009951.g002
DOI:
10.1371/journal.pntd.0009951.g003
DOI:
10.1371/journal.pntd.0009951.g004
DOI:
10.1371/journal.pntd.0009951.g005
DOI:
10.1371/journal.pntd.0009951.g006
DOI:
10.1371/journal.pntd.0009951.s001
DOI:
10.1371/journal.pntd.0009951.s002
DOI:
10.1371/journal.pntd.0009951.s003
DOI:
10.1371/journal.pntd.0009951.s004
DOI:
10.1371/journal.pntd.0009951.s005
DOI:
10.1371/journal.pntd.0009951.s006
DOI:
10.1371/journal.pntd.0009951.s007
DOI:
10.1371/journal.pntd.0009951.s008
DOI:
10.1371/journal.pntd.0009951.s009
DOI:
10.1371/journal.pntd.0009951.s010
DOI:
10.1371/journal.pntd.0009951.s011
DOI:
10.1371/journal.pntd.0009951.s012
DOI:
10.1371/journal.pntd.0009951.s013
DOI:
10.1371/journal.pntd.0009951.s014
DOI:
10.1371/journal.pntd.0009951.s015
DOI:
10.1371/journal.pntd.0009951.r001
DOI:
10.1371/journal.pntd.0009951.r002
DOI:
10.1371/journal.pntd.0009951.r003
DOI:
10.1371/journal.pntd.0009951.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2429704-5
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