Chalcones identify cTXNPx as a potential antileishmanial drug target.

• Published in: PLOS Neglected Tropical Diseases
• Main Authors: Douglas O Escrivani, Rebecca L Charlton, Marjolly B Caruso, Gabriela A Burle-Caldas, Maria Paula G Borsodi, Russolina B Zingali, Natalia Arruda-Costa, Marcos V Palmeira-Mello, Jéssica B de Jesus, Alessandra M T Souza, Bárbara Abrahim-Vieira, Stefanie Freitag-Pohl, Ehmke Pohl, Paul W Denny, Bartira Rossi-Bergmann, Patrick G Steel
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science (PLoS) 2021
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Public aspects of medicine; RA1-1270; Arctic
• Online Access: https://doi.org/10.1371/journal.pntd.0009951; https://doaj.org/article/97dcebeea4914662b9ca60f477d72118

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.