ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species

Zhou, Linna; Ishizaki, Hironori; Spitzer, Michaela; Taylor, Kerrie L.; Temperley, Nicholas D.; Johnson, Stephen L.; Brear, P.; Gautier, Philippe; Zeng, Zhiqiang; Mitchell, Amy L.; Narayan, Vikram; McNeil, Ewan M.; Melton, David W.; Smith, Terry; Tyers, Mike; Westwood, Nicholas J.; Patton, E. Elizabeth

doi:10.1016/j.chembiol.2012.05.017

Cited by 51 publications

(30 citation statements)

References 42 publications

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“…However, 5-nitrofuran has considerable human toxicity (99). Interestingly, 5-nitrofuran directly binds to and dose-dependently inhibits human ALDH2 activity, suggesting 5-nitrofuran prodrug activation depends on ALDH2 in humans (100). Zebra fish and yeast model systems have also been used to show ALDH2 inhibition reduces 5-nitrofuran toxicity (100).…”

Section: Drug Considerations For People With the Aldh2*2 Variantmentioning

confidence: 99%

“…Interestingly, 5-nitrofuran directly binds to and dose-dependently inhibits human ALDH2 activity, suggesting 5-nitrofuran prodrug activation depends on ALDH2 in humans (100). Zebra fish and yeast model systems have also been used to show ALDH2 inhibition reduces 5-nitrofuran toxicity (100). Because 5-nitrofuran is being investigated for treating medulloblastoma and neuroblastoma (101), further studies will be needed to investigate whether this drug is effective in treating these diseases in patients with the ALDH2*2 variant.…”

Section: Drug Considerations For People With the Aldh2*2 Variantmentioning

confidence: 99%

See 1 more Smart Citation

A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant

Gross

Zambelli²,

Small³

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

116

122

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Asian Americans are one of the fastest-growing populations in the United States. A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2. Found in approximately 560 million people of East Asian descent, ALDH2*2 reduces enzymatic activity by approximately 60% to 80% in heterozygotes. Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis. In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant. We also discuss future clinical and translational perspectives regarding ALDH2*2 research.

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Section: Drug Considerations For People With the Aldh2*2 Variantmentioning

confidence: 99%

Section: Drug Considerations For People With the Aldh2*2 Variantmentioning

confidence: 99%

A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant

Gross

Zambelli²,

Small³

et al. 2015

Annu. Rev. Pharmacol. Toxicol.

116

122

View full text Add to dashboard Cite

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“…In this study, we report that our recently discovered nitrofuran NFN1 ( 12a ) 17 also shows promising activity against T. brucei in vitro . We have therefore synthesized a series of 5-nitro-2-furancarboxylamide analogues of 12a .…”

Section: Introductionmentioning

confidence: 77%

“…14−16 Recently, we have elucidated in collaboration with the Patton Laboratory a possible role of aldehyde dehydrogenase 2 (ALDH2) in the toxicity caused by 5-nitrofuran containing drugs such as nifurtimox. 17 …”

Section: Introductionmentioning

confidence: 99%

A Class of 5-Nitro-2-furancarboxylamides with Potent Trypanocidal Activity againstTrypanosoma bruceiin Vitro

et al. 2013

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Recently, the World Health Organization approved the nifurtimox–eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases. In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, ∼1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells. More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa. This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites. The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance. Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness.

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“…We also screened two custom Yeast Bioactive Collections, termed Bioactive 1 and Bioactive 2, both of which were derived from screens of a 53,000 compound synthetic library (Ryan Scientific) in an S. cerevisiae cell proliferation assay at 10 μM (refs 16,17). The Bioactive 1 library contained 678 compounds that inhibited growth of a pdr1 Δ̣ pdr3 Δ strain between 20% and 80%.…”

Section: Methodsmentioning

confidence: 99%

Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism

et al. 2016

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The network structure of biological systems suggests that effective therapeutic intervention may require combinations of agents that act synergistically. However, a dearth of systematic chemical combination datasets have limited the development of predictive algorithms for chemical synergism. Here, we report two large datasets of linked chemical-genetic and chemical-chemical interactions in the budding yeast Saccharomyces cerevisiae. We screened 5,518 unique compounds against 242 diverse yeast gene deletion strains to generate an extended chemical-genetic matrix (CGM) of 492,126 chemical-gene interaction measurements. This CGM dataset contained 1,434 genotype-specific inhibitors, termed cryptagens. We selected 128 structurally diverse cryptagens and tested all pairwise combinations to generate a benchmark dataset of 8,128 pairwise chemical-chemical interaction tests for synergy prediction, termed the cryptagen matrix (CM). An accompanying database resource called ChemGRID was developed to enable analysis, visualisation and downloads of all data. The CGM and CM datasets will facilitate the benchmarking of computational approaches for synergy prediction, as well as chemical structure-activity relationship models for anti-fungal drug discovery.

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ALDH2 Mediates 5-Nitrofuran Activity in Multiple Species

Cited by 51 publications

References 42 publications

A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant

A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant

A Class of 5-Nitro-2-furancarboxylamides with Potent Trypanocidal Activity againstTrypanosoma bruceiin Vitro

Systematic chemical-genetic and chemical-chemical interaction datasets for prediction of compound synergism

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