Chemotherapeutic efficacy of ascofuranone in Trypanosoma vivax-infected mice without glycerol

Yabu, Yoshisada; Suzuki, Takashi; Nihei, Coh-ichi; Minagawa, Nobuko; Hosokawa, Tomoyoshi; Nagai, Kazuo; Kita, Kiyoshi; Ohta, Nobuhiro

doi:10.1016/j.parint.2005.09.003

Cited by 49 publications

(47 citation statements)

References 51 publications

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“…Indeed, we have previously reported that the antibiotic ascofuranone (AF), isolated from the pathogenic fungus Ascochyta viciae, specifically inhibits the quinol oxidase activity of TAO at subnanomolar concentrations and rapidly kills the parasites (10). Furthermore, we have confirmed the chemotherapeutic efficacy of ascofuranone in vivo (11,12).…”

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confidence: 58%

Structure of the trypanosome cyanide-insensitive alternative oxidase

Shiba¹,

Kido²,

Sakamoto³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In addition to haem copper oxidases, all higher plants, some algae, yeasts, molds, metazoans, and pathogenic microorganisms such as Trypanosoma brucei contain an additional terminal oxidase, the cyanide-insensitive alternative oxidase (AOX). AOX is a diiron carboxylate protein that catalyzes the four-electron reduction of dioxygen to water by ubiquinol. In T. brucei, a parasite that causes human African sleeping sickness, AOX plays a critical role in the survival of the parasite in its bloodstream form. Because AOX is absent from mammals, this protein represents a unique and promising therapeutic target. Despite its bioenergetic and medical importance, however, structural features of any AOX are yet to be elucidated. Here we report crystal structures of the trypanosomal alternative oxidase in the absence and presence of ascofuranone derivatives. All structures reveal that the oxidase is a homodimer with the nonhaem diiron carboxylate active site buried within a four-helix bundle. Unusually, the active site is ligated solely by four glutamate residues in its oxidized inhibitor-free state; however, inhibitor binding induces the ligation of a histidine residue. A highly conserved Tyr220 is within 4 Å of the active site and is critical for catalytic activity. All structures also reveal that there are two hydrophobic cavities per monomer. Both inhibitors bind to one cavity within 4 Å and 5 Å of the active site and Tyr220, respectively. A second cavity interacts with the inhibitor-binding cavity at the diiron center. We suggest that both cavities bind ubiquinol and along with Tyr220 are required for the catalytic cycle for O 2 reduction. diiron protein | neglected tropical diseases | monotopic membrane protein | drug target | ubiquinol oxidase

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mentioning

confidence: 58%

Structure of the trypanosome cyanide-insensitive alternative oxidase

Shiba¹,

Kido²,

Sakamoto³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

158

209

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“…Thus the necessary dosage of glycerol is considered to be low for the treatment of T. vivax-infected animals together with AF. Indeed as mentioned above, oral treatment of 100 mg/kg AF could cure T. vivax-infected mice without glycerol [16]. Finally, obtained profiles for GK molecules may not directly correspond with those in vivo trypanosome cells, since we used culture-adapted trypanosome strains in the present study.…”

Section: Discussionmentioning

confidence: 88%

“…For T. vivax, oral treatment of 100 mg/kg AF could cure T. vivax-infected mice without glycerol [16]. However, for T. congolense, oral treatment with 300 mg/kg AF and 3 g/kg glycerol using the same protocol with Yabu et al [15] could not cure T. congolense-infected mice, and the trypanocidal effect of 300 mg/kg AF was not significantly enhanced by 3 g/kg glycerol (Suzuki et al unpublished data).…”

Section: In Vitro Combination Trials Of Af and Glycerol For Each Trypmentioning

confidence: 99%

Differential Kinetic Activities of Glycerol Kinase among African Trypanosome Species: Phylogenetic and Therapeutic Implications

et al. 2011

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ABSTRACT. African trypanosome species are causative agents for sleeping sickness in humans and nagana disease in cattle. Trypanosoma brucei can generate ATP via a reverse reaction with glycerol kinase (GK) when alternative oxidase (AOX) is inhibited; thus, GK is considered to be a crucial target for chemotherapy combined with AOX. However, the energy metabolism systems of African trypanosome species other than T. brucei are poorly understood. Thus, GK genes were surveyed from genome databases and cloned by PCR from T. vivax and T. congolense. Then, recombinant GK proteins (rGK) of T. vivax, T. congolense and T. brucei were expressed and purified. Kinetic analysis of these rGK proteins revealed that the K m values of T. congolense rGK for ADP and G-3-P substrates were lower than those of T. vivax and T. brucei. The expression level of GK molecules was highest in T. congolense cells and lowest in T. vivax cells. Based on these results, effective combination dosages of ascofuranone, a specific inhibitor of AOX, and glycerol, an inhibitor of the GK reverse reaction, were determined by using in vitro-cultured trypanosome cells.

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“…Notably, two recent reports on the TAO inhibitor ascofuranone (77,78) have shown that this compound has therapeutic properties in mice infected with either T. brucei or T. vivax. Cordycepin and quercetin, drugs under preclinical studies, showed strong effects against T. b. gambiense.…”

Section: Drugs Targeted To Mitochondriamentioning

confidence: 99%

Mitochondria and Trypanosomatids: Targets and Drugs

2011

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The family Trypanosomatidae, flagellated parasitic protozoa, is responsible for important infectious diseases in humans: sleeping sickness, Chagas diseases and leishmaniasis. Currently, development of effective vaccines against these parasites remains an unrealized goal, and clinical management is based on chemotherapeutics. Cost, toxicity and resistance problems of conventional drugs result in an urgent need to identify and develop new therapeutic alternatives. The sound understanding of parasites, biology is key for identifying novel lead structures and new drug targets. This article reviews current knowledge about mitochondrial drug targets and existing drugs against Trypanosoma and Leishmania. In the past, several targets in trypanosomatid mitochondria (electron transport chain, kDNA and topoisomerases, tRNA import and fatty acid synthesis) have been identified. It has been suggested that inhibition of certain targets is involved in triggering apoptosis by impairment of mitochondrial membrane potential and/or production of reactive oxygen species. The inhibitory mechanism of approved drugs, such as pentamidine, nifurtimox, artemisinin and atovaquone, is described in parallel with others products from preclinical studies. In spite of the large amount of genetic information, the analysis of the phenotype of the trypanosomatid mitochondrion in different life stages will remain a useful tool to design new active compounds with selective toxicity against these parasites.

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Chemotherapeutic efficacy of ascofuranone in Trypanosoma vivax-infected mice without glycerol

Cited by 49 publications

References 51 publications

Structure of the trypanosome cyanide-insensitive alternative oxidase

Structure of the trypanosome cyanide-insensitive alternative oxidase

Differential Kinetic Activities of Glycerol Kinase among African Trypanosome Species: Phylogenetic and Therapeutic Implications

Mitochondria and Trypanosomatids: Targets and Drugs

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