In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 2 ( 2021-2-4), p. e0243855-
Abstract:
Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi ( T . cruzi ). It was originally a Latin American endemic health problem, but now is expanding worldwide as a result of increasing migration. The currently available drugs for Chagas disease, benznidazole and nifurtimox, provoke severe adverse effects, and thus the development of new drugs is urgently required. Ubiquinone (UQ) is essential for respiratory chain and redox balance in trypanosomatid protozoans, therefore we aimed to provide evidence that inhibitors of the UQ biosynthesis have trypanocidal activities. In this study, inhibitors of the human COQ7, a key enzyme of the UQ synthesis, were tested for their trypanocidal activities because they were expected to cross-react and inhibit trypanosomal COQ7 due to their genetic homology. We show the trypanocidal activity of a newly found human COQ7 inhibitor, an oxazinoquinoline derivative. The structurally similar compounds were selected from the commercially available compounds by 2D and 3D ligand-based similarity searches. Among 38 compounds selected, 12 compounds with the oxazinoquinoline structure inhibited significantly the growth of epimastigotes of T . cruzi . The most effective 3 compounds also showed the significant antitrypanosomal activity against the mammalian stage of T . cruzi at lower concentrations than benznidazole, a commonly used drug today. We found that epimastigotes treated with the inhibitor contained reduced levels of UQ 9 . Further, the growth of epimastigotes treated with the inhibitors was partially rescued by UQ 10 supplementation to the culture medium. These results suggest that the antitrypanosomal mechanism of the oxazinoquinoline derivatives results from inhibition of the trypanosomal UQ synthesis leading to a shortage of the UQ pool. Our data indicate that the UQ synthesis pathway of T . cruzi is a promising drug target for Chagas disease.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0243855
DOI:
10.1371/journal.pone.0243855.g001
DOI:
10.1371/journal.pone.0243855.g002
DOI:
10.1371/journal.pone.0243855.g003
DOI:
10.1371/journal.pone.0243855.g004
DOI:
10.1371/journal.pone.0243855.g005
DOI:
10.1371/journal.pone.0243855.g006
DOI:
10.1371/journal.pone.0243855.g007
DOI:
10.1371/journal.pone.0243855.g008
DOI:
10.1371/journal.pone.0243855.g009
DOI:
10.1371/journal.pone.0243855.t001
DOI:
10.1371/journal.pone.0243855.t002
DOI:
10.1371/journal.pone.0243855.s001
DOI:
10.1371/journal.pone.0243855.s002
DOI:
10.1371/journal.pone.0243855.s003
DOI:
10.1371/journal.pone.0243855.s004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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