Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration.

Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Research Abstract Details 

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Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Abstract Text:

Robert Ott,Kelly Chibale,Sedrick Anderson,Alex Chipeleme,Minu Chaudhuri,Abdelmadjid Guerrah,Nancy Colowick,George C Hill,

African trypanosomiasis is a deadly disease for which few chemotherapeutic options are available. The causative agents, Trypanosoma brucei rhodesiense and T. b. gambiense, utilize a non-cytochrome, alternative oxidase (AOX) for their cellular respiration. The absence of this enzyme in mammalian cells makes it a logical target for therapeutic agents. We designed three novel compounds, ACB41, ACD15, and ACD16, and investigated their effects on trypanosome alternative oxidase (TAO) enzymatic activity, parasite respiration, and parasite growth in vitro. All three compounds contain a 2-hydroxybenzoic acid moiety, analogous to that present in SHAM, and a prenyl side chain similar to that found in ubiquinol. ACD15 and ACD16 are further differentiated by the presence of a solubility-enhancing carbohydrate moiety. Kinetic studies with purified TAO show that all three compounds competitively inhibit TAO, and two compounds, ACB41 and ACD15, have inhibition constants five- and three-fold more potent than SHAM, respectively. All three compounds inhibited the respiration and growth of continuously cultured T. b. brucei bloodstream cells in a dose-dependent manner. None of the compounds interfered with respiration of rat liver mitochondria, nor did they inhibit the growth of a continuously cultured mammalian cell line. Collectively, the results suggest we have identified a new class of compounds that are inhibitors of TAO, have trypanocidal properties in vitro, and warrant further investigation in vivo.

Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Publishing Authors By Initials

R Ott,K Chibale,S Anderson,A Chipeleme,M Chaudhuri,A Guerrah,N Colowick,GC Hill,

For similar animals: invertebrates: protozoa: sarcomastigophora: mastigophora: zoomastigophora: kinetoplastida: trypanosomatina: trypanosoma: trypanosoma brucei brucei research abstracts see: animals: invertebrates: protozoa: sarcomastigophora: mastigophora: zoomastigophora: kinetoplastida: trypanosomatina: trypanosoma: trypanosoma brucei brucei research

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Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Acta tropica

VOLUME: 100

Page Numbers: 172-84

Journal Abbreviation: Acta Trop.

ISSN: 0001-706X

DAY: 28

MONTH: 11

YEAR: 2006

Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Information

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LANGUAGE: eng

NlmUniqueID: 370374

Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Keywords Mesh Terms:

KEYWORDS: Trypanosoma brucei brucei

MESH TERMS: metabolism

Chemical & Substance for Abstract: Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration. Information

Substance Name: alternative oxidase

Registry Number: EC 1.-

Grant and Affiliation Information for Novel inhibitors of the trypanosome alternative oxidase inhibit Trypanosoma brucei brucei growth and respiration.

AFFILIATION: Vanderbilt University School of Medicine, Department of Microbiology and Immunology, Nashville, TN 37232, United States.

Country: Netherlands

AGENCY: United States NIGMS

GRANT: F06GM08037

ACRONYM: GM

MEDLINETA: Acta Trop

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