Open AccessChalcones identify cTXNPx as a potential antileishmanial drug target
Author(s) -
Douglas O. Escrivani,
Rebecca L Charlton,
Marjolly Brígido Caruso,
Gabriela A. Burle-Caldas,
Maria Paula Gonçalves Borsodi,
Russolina B. Zingali,
Marcos V. Palmeira-Mello,
Jéssica Barbosa de Jesus,
Alessandra Mendonça Teles de Souza,
Bárbara Abrahim-Vieira,
Stefanie Freitag-Pohl,
Ehmke Pohl,
Paul W. Denny,
Bartira RossiBergmann,
Patrick G. Steel
Publication year - 2021
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0009951
Subject(s) - chalcone , amastigote , biology , leishmaniasis , leishmania infantum , in silico , biochemistry , pharmacology , leishmania , chemistry , visceral leishmaniasis , parasite hosting , immunology , stereochemistry , world wide web , computer science , gene
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.