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Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei.
J Biol Chem. 2013 Sep 20; 288(38):27456-68.JB

Abstract

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.

Authors+Show Affiliations

From the Division of Biochemistry, Department of Medical Biochemistry and Biophysics, and.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23900839

Citation

Lu, Jun, et al. "Ebsulfur Is a Benzisothiazolone Cytocidal Inhibitor Targeting the Trypanothione Reductase of Trypanosoma Brucei." The Journal of Biological Chemistry, vol. 288, no. 38, 2013, pp. 27456-68.
Lu J, Vodnala SK, Gustavsson AL, et al. Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei. J Biol Chem. 2013;288(38):27456-68.
Lu, J., Vodnala, S. K., Gustavsson, A. L., Gustafsson, T. N., Sjöberg, B., Johansson, H. A., Kumar, S., Tjernberg, A., Engman, L., Rottenberg, M. E., & Holmgren, A. (2013). Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei. The Journal of Biological Chemistry, 288(38), 27456-68. https://doi.org/10.1074/jbc.M113.495101
Lu J, et al. Ebsulfur Is a Benzisothiazolone Cytocidal Inhibitor Targeting the Trypanothione Reductase of Trypanosoma Brucei. J Biol Chem. 2013 Sep 20;288(38):27456-68. PubMed PMID: 23900839.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei. AU - Lu,Jun, AU - Vodnala,Suman K, AU - Gustavsson,Anna-Lena, AU - Gustafsson,Tomas N, AU - Sjöberg,Birger, AU - Johansson,Henrik A, AU - Kumar,Sangit, AU - Tjernberg,Agneta, AU - Engman,Lars, AU - Rottenberg,Martin E, AU - Holmgren,Arne, Y1 - 2013/07/29/ PY - 2013/8/1/entrez PY - 2013/8/1/pubmed PY - 2013/12/16/medline KW - Drug Development KW - Enzyme Inhibitors KW - Parasite KW - Reactive Oxygen Species (ROS) KW - Thiol KW - Thioredoxin SP - 27456 EP - 68 JF - The Journal of biological chemistry JO - J Biol Chem VL - 288 IS - 38 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/23900839/Ebsulfur_is_a_benzisothiazolone_cytocidal_inhibitor_targeting_the_trypanothione_reductase_of_Trypanosoma_brucei_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=23900839 DB - PRIME DP - Unbound Medicine ER -