Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

Moya-Garzón, María Dolores; Gómez-Vidal, José A.; Alejo-Armijo, Alfonso; Altarejos, Joaquı́n; Rodríguez-Madoz, Juan R.; Fernandes, Miguel X.; Salido, Sofı́a; Díaz‐Gavilán, Mónica

doi:10.3390/jpm11020074

Cited by 19 publications

(17 citation statements)

References 217 publications

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“…Currently, the only approved therapeutic modality for hHAO1 inhibition is RNAi. Existing small molecules in development include chemical series of pyrazole ( Barawkar et al, 2012 ; Chen et al, 2012 ; Bourhis et al, 2009 ), triazole ( Stenberg and Lindqvist 1997 ; Murray et al, 2008 ), or salicylate ( Moya-Garzón et al, 2018 ) backbones and generally consist of a carboxylic acid like moiety mimicking the substrate carboxylic acid and one or more heterocyclic rings that pi stack with FMN (recently reviewed by ( Moya-Garzon et al, 2021 )).…”

Section: Discussionmentioning

confidence: 99%

Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening

et al. 2022

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Primary hyperoxaluria type I (PH1) is caused by AGXT gene mutations that decrease the functional activity of alanine:glyoxylate aminotransferase. A build-up of the enzyme’s substrate, glyoxylate, results in excessive deposition of calcium oxalate crystals in the renal tract, leading to debilitating renal failure. Oxidation of glycolate by glycolate oxidase (or hydroxy acid oxidase 1, HAO1) is a major cellular source of glyoxylate, and siRNA studies have shown phenotypic rescue of PH1 by the knockdown of HAO1, representing a promising inhibitor target. Here, we report the discovery and optimization of six low-molecular-weight fragments, identified by crystallography-based fragment screening, that bind to two different sites on the HAO1 structure: at the active site and an allosteric pocket above the active site. The active site fragments expand known scaffolds for substrate-mimetic inhibitors to include more chemically attractive molecules. The allosteric fragments represent the first report of non-orthosteric inhibition of any hydroxy acid oxidase and hold significant promise for improving inhibitor selectivity. The fragment hits were verified to bind and inhibit HAO1 in solution by fluorescence-based activity assay and surface plasmon resonance. Further optimization cycle by crystallography and biophysical assays have generated two hit compounds of micromolar (44 and 158 µM) potency that do not compete with the substrate and provide attractive starting points for the development of potent and selective HAO1 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening

et al. 2022

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“… 59–62 Other strategies that target the underlying metabolic defect of PH currently under development and/or investigation are: substrate reduction therapies as such as the one using CRISPR/Cas9 technologies targeting either glycolate oxidase or lactate dehydrogenase, replacement therapies such as gene therapy, cell therapy and enzyme replacement therapy; pharmacological chaperone therapy. 63 On the other hand, since the deposition of calcium oxalate (CaOx) crystals in the kidney leads to the activation of several pathways that mediate kidney damage, strategies that aim to treat renal manifestations of PH are also under development (anti-inflammatory, anti-fibrotic and crystallization preventing therapies). 3 , 63 …”

Section: Novel Therapiesmentioning

confidence: 99%

“… 63 On the other hand, since the deposition of calcium oxalate (CaOx) crystals in the kidney leads to the activation of several pathways that mediate kidney damage, strategies that aim to treat renal manifestations of PH are also under development (anti-inflammatory, anti-fibrotic and crystallization preventing therapies). 3 , 63 …”

Section: Novel Therapiesmentioning

confidence: 99%

Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside

D’Ambrosio¹,

Ferraro²

2022

IJNRD

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Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent nephrolithiasis, nephrocalcinosis and, eventually, kidney failure. As glomerular filtration rate declines, oxalate accumulates leading to systemic oxalosis, a debilitating condition with high morbidity and mortality. Although PH is usually diagnosed during infancy, it can present at any age with different phenotypes, ranging from mild symptoms to extremely debilitating manifestations. PH is an autosomal recessive disorder and, to date, three types have been identified: PH1, PH2 and PH3. PH1 is the most common and most aggressive type, accounting for almost 80% of primary hyperoxaluria diagnoses. Until 2020, general treatment for PH1 consisted mainly in high fluid intake, urine alkalization, surgical management of recurrent nephrolithiasis and eventually, if and when kidney failure occurred, intensive dialysis regimens and transplantation strategies (simultaneous or sequential liver-kidney transplant or isolated liver/kidney transplant in carefully selected patients). Specific treatment did and still consists in administration of pyridoxine hydrochloride, although it is only effective in a subset of PH1 patients. Lumasiran, a novel biological drug based on mRNA interference that has been recently approved in the US and European Union, showed promising results and is set to be a turning point in the management of PH1. This literature review aims to summarize the available evidence on PH1 treatment with lumasiran, in order to provide both pediatric and adult nephrologists and clinicians with the knowledge for the identification and management of PH1 patients suitable for treatment.

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“…However, some authors have challenged this observation [ 20 , 21 ], and clinical trials are ongoing to prove its efficacy in PH1. Other small molecules are in the pipeline, including oral small molecule inhibitors to LDH or GO, or chaperones for misfolded enzymes to restore function, but these remain at the stage of pre-clinical experimentation [ 22 , 23 ].…”

Section: Other Therapeutic Perspectivesmentioning

confidence: 99%

Primary hyperoxaluria type 1: novel therapies at a glance

Bacchetta¹,

Lieske

2022

Clinical Kidney Journal

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Primary hyperoxaluria type 1 (PH1) is a rare and severe autosomal recessive disease of oxalate metabolism, resulting from a mutation in the AGXT gene that encodes the hepatic peroxisomal enzyme alanine–glyoxylate aminotransferase (AGT). Until recently, treatment of PH1 was supportive, consisting of intensive hyperhydration, use of crystallization inhibitors (citrate and neutral phosphorus), in a subset of responsive PH1 patients’ pharmacologic doses of vitamin B6 (pyridoxine), and kidney and liver transplantation when patients progressed to kidney failure. Treatment approaches have been similar for PH2 caused by mutations in hepatic glyoxylate reductase/hydroxypyruvate reductase (GR/HPR), although pyridoxine does not have any benefit in this group. PH3 is caused by mutations of mitochondrial 4-hydroxy-2-oxoglutarate aldolase (HOGA1) and was the most recently described. Kidney failure appears less common in PH3, although kidney stones occur as frequently as in PH1 and PH2. Oxalate metabolism in the liver is complex. Novel therapies based on RNA interference (RNAi) have recently emerged to modulate these pathways, designed to deplete substrate for enzymes upstream and decrease/avoid oxalate production. Two hepatic enzymes have been targeted to date in PH: glycolate oxidase (GO) with lumasiran and lactate dehydrogenase A (LDH-A) with nedosiran. Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst clinical trials with nedosiran are ongoing. Results with the two RNAi therapies demonstrate a significant reduction of urinary oxalate excretion in PH1 patients, but long-term data on efficacy (preservation of kidney function, decreased stone events) and safety remain to be established. Nevertheless, the hepatically targeted RNAi approach represents a potential ‘game changer’ in the field of PH1, bringing hope to families and patients that they may be able to avoid liver and/or kidney transplantation in the future and suffer fewer stone events, perhaps with less strict therapeutic regimens. Pharmacological compounds directly inhibiting GO or LDH are also under development and could be of special interest in developing countries where RNAi therapies may not be readily available in the near future. Approaches to manipulate the intestinal microbiome with a goal to increase oxalate degradation or to stimulate secretion of oxalate into the intestine from plasma are also under development. Overall, we appear to be entering a new phase of PH treatment, with an array of promising approaches emerging that will need optimization and evaluation to establish long-term efficacy and safety.

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Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

Cited by 19 publications

References 217 publications

Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening

Novel Starting Points for Human Glycolate Oxidase Inhibitors, Revealed by Crystallography-Based Fragment Screening

Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside

Primary hyperoxaluria type 1: novel therapies at a glance

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