Chalcones identify cTXNPx as a potential antileishmanial drug target.

Autor: Escrivani DO; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.; Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, United Kingdom., Charlton RL; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.; Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, United Kingdom., Caruso MB; Instituto de Bioquímica Médica Leopoldo de Meis (IBqM), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Burle-Caldas GA; Department of Biosciences, Durham University, Science Laboratories, South Road, Durham, United Kingdom., Borsodi MPG; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Zingali RB; Instituto de Bioquímica Médica Leopoldo de Meis (IBqM), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Arruda-Costa N; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Palmeira-Mello MV; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., de Jesus JB; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Souza AMT; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Abrahim-Vieira B; Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Freitag-Pohl S; Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, United Kingdom., Pohl E; Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, United Kingdom.; Department of Biosciences, Durham University, Science Laboratories, South Road, Durham, United Kingdom., Denny PW; Department of Biosciences, Durham University, Science Laboratories, South Road, Durham, United Kingdom., Rossi-Bergmann B; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Steel PG; Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2021 Nov 15; Vol. 15 (11), pp. e0009951. Date of Electronic Publication: 2021 Nov 15 (Print Publication: 2021).
DOI: 10.1371/journal.pntd.0009951
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje