High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

Chen, Zhiwei; Vignaud, Caroline; Jaafar, A.; Levy, Bernard C.; Guéritte, Françoise; Guénard, Daniel; Lederer, Florence; Mathews, F.S.

doi:10.1016/j.biochi.2012.02.003

Cited by 19 publications

(24 citation statements)

References 41 publications

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“…Subsequently, it was suggested that the most appealing target should be to develop specific inhibitors of HAO1, encoding glycolate oxidase, as this is a non-essential metabolic pathway leading to glyoxylate 5. HAO1 inhibitors are currently being developed as potential treatment for primary hyperoxaluria type 1 8 15. However, the consequences of depletion of activity of this enzyme in humans remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Mutations inHAO1encoding glycolate oxidase cause isolated glycolic aciduria

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Mutations inHAO1encoding glycolate oxidase cause isolated glycolic aciduria

et al. 2014

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“…CCPST, a GO Inhibitor, Blunts Oxalate Production in Primary Cultures of PH1 Mouse Hepatocytes CCPST has been previously described as an inhibitor of human GO 9 as well as the rat isozyme long-chain hydroxy acid oxidase. 12 We have expressed and purified mouse recombinant GO (Supplementary Figure S2) to assess the inhibitory effect of CCPST on mouse GO (mGO). Various concentrations of commercial CCPST were tested on a constant amount of GO protein at each concentration of glycolate.…”

Section: Go Deficiency Reverses the Hyperoxaluric Phenotype In Ph1 Micementioning

confidence: 99%

Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I

2016

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Primary hyperoxaluria type 1 (PH1) is caused by deficient alanine-glyoxylate aminotransferase, the human peroxisomal enzyme that detoxifies glyoxylate. Glycolate is one of the best-known substrates leading to glyoxylate production, via peroxisomal glycolate oxidase (GO). Using genetically modified mice, we herein report GO as a safe and efficient target for substrate reduction therapy (SRT) in PH1. We first generated a GO-deficient mouse (Hao1(-/-)) that presented high urine glycolate levels but no additional phenotype. Next, we produced double KO mice (Agxt1(-/-) Hao1(-/-)) that showed low levels of oxalate excretion compared with hyperoxaluric mice model (Agxt1(-/-)). Previous studies have identified some GO inhibitors, such as 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1,2,3-thiadiazole (CCPST). We herein report that CCPST inhibits GO in Agxt1(-/-) hepatocytes and significantly reduces their oxalate production, starting at 25 µM. We also tested the ability of orally administered CCPST to reduce oxalate excretion in Agxt1(-/-) mice, showing that 30-50% reduction in urine oxalate can be achieved. In summary, we present proof-of-concept evidence for SRT in PH1. These encouraging results should be followed by a medicinal chemistry programme that might yield more potent GO inhibitors and eventually could result in a pharmacological treatment for this rare and severe inborn error of metabolism.

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“…Inhibiting glycolate oxidase (GO), a hepatic, peroxisomal enzyme upstream of AGT, is one possible mechanism for depleting diseased livers of substrate for oxalate synthesis, to potentially prevent the pathology that develops in PH1. [10][11][12][13] GO, encoded by the hydroxyacid oxidase (HAO1) gene, catalyzes the oxidation of glycolate to glyoxylate, the immediate precursor to oxalate synthesis in hepatocytes ( Figure 1). Suppression of GO activity should inhibit oxalate production while causing an accumulation of glycolate.…”

mentioning

confidence: 99%

An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria

Liebow

Racie

et al. 2016

JASN

177

147

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Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.

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High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

Cited by 19 publications

References 41 publications

Mutations inHAO1encoding glycolate oxidase cause isolated glycolic aciduria

Mutations inHAO1encoding glycolate oxidase cause isolated glycolic aciduria

Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I

An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria

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