id:"swepub:oai:DiVA.org:uu-208116"
Search: id:"swepub:oai:DiVA.org:uu-208116" > Ebsulfur is a benzi...
- 1 of 1
- Previous record
- Next record
- To hitlist
Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei
-
- Lu, Jun (author)
- Karolinska Institutet
- Vodnala, Suman K. (author)
-
- Gustavsson, Anna-Lena (author)
- Karolinska Institutet
- show more...
- Kumar, Sangit (author)
- Tjernberg, Agneta (author)
- show less...
- (creator_code:org_t)
- 2013
- 2013
- English.
- In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 288:38, s. 27456-27468
- Journal article (peer-reviewed)
Abstract
Subject headings
Close
- Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
- Journal of Biological Chemistry (Search for host publication in LIBRIS)
To the university's database
- 1 of 1
- Previous record
- Next record
- To hitlist
Find more in SwePub
- By the author/editor
- Lu, Jun
- Vodnala, Suman K ...
- Gustavsson, Anna ...
- Gustafsson, Toma ...
- Sjöberg, Birger
- Johansson, Henri ...
- show more...
- Kumar, Sangit
- Tjernberg, Agnet ...
- Engman, Lars
- Rottenberg, Mart ...
- Holmgren, Arne
- show less...
- Articles in the publication
- Journal of Biolo ...
- By the university
- Uppsala University
- Karolinska Institutet
Search outside SwePub
- Extend your search to:
- Google Book Search
- Google Scholar
Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.
- Copyright © LIBRIS - National Library Systems
- LIBRIS.kb.se
