TY - JOUR
T1 - Chalcones identify cTXNPx as a potential antileishmanial drug target
AU - Escrivani, Douglas O
AU - Charlton, Rebecca L
AU - Caruso, Marjolly B
AU - Burle-Caldas, Gabriela A
AU - Borsodi, Maria Paula G
AU - Zingali, Russolina B
AU - Arruda-Costa, Natalia
AU - Palmeira-Mello, Marcos V
AU - de Jesus, Jéssica B
AU - Souza, Alessandra M T
AU - Abrahim-Vieira, Bárbara
AU - Freitag-Pohl, Stefanie
AU - Pohl, Ehmke
AU - Denny, Paul W
AU - Rossi-Bergmann, Bartira
AU - Steel, Patrick G
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - Animals
KW - Antiprotozoal Agents/administration & dosage
KW - Cells, Cultured
KW - Chalcone/administration & dosage
KW - Cytosol/drug effects
KW - Drug Discovery
KW - Humans
KW - Leishmania/classification
KW - Leishmaniasis/drug therapy
KW - Macrophages/drug effects
KW - Mice
KW - Mice, Inbred BALB C
KW - Molecular Docking Simulation
KW - Peroxidases/antagonists & inhibitors
KW - Protozoan Proteins/antagonists & inhibitors
U2 - 10.1371/journal.pntd.0009951
DO - 10.1371/journal.pntd.0009951
M3 - Article
C2 - 34780470
SN - 1935-2727
VL - 15
SP - e0009951
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
IS - 11
ER -