High-Throughput Screen Fails to Identify Compounds That Enhance Residual Enzyme Activity of Mutant N-Acetyl-α-Glucosaminidase in Mucopolysaccharidosis Type IIIB

Meijer, O. L. M.; Biggelaar, P. van den; Ofman, Rob; Wijburg, Frits A.; Vlies, Naomi van

doi:10.1007/8904_2017_51

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…[20] Consequently, both atovaquone and piperaquine were identified as more efficient PCs for the NAGLU enzyme compared to the iminosugars. Finally, it is important to mention the study by Meijer et al, [21] who were unable to identify pharmacological chaperones for MPS IIIB through high-throughput screening. The authors evaluated the effect of 1,302 different molecules on the residual NAGLU activity in p.S612G MPSIIIB fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB

Losada,

Triana,

Vanegas

et al. 2024

ChemBioChem

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Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal inherited disease caused by mutations in gene encoding the lysosomal enzyme N‐acetyl‐alpha‐glucosaminidase (NAGLU). These mutations result in reduced NAGLU activity, preventing it from catalyzing the hydrolysis of the glycosaminoglycan heparan sulfate (HS). There are currently no approved treatments for MPS IIIB. A novel approach in the treatment of lysosomal storage diseases is the use of pharmacological chaperones (PC). In this study, we used a drug repurposing approach to identify and characterize novel potential PCs for NAGLU enzyme. We modeled the interaction of natural and artificial substrates within the active cavity of NAGLU (orthosteric site) and predicted potential allosteric sites. We performed a virtual screening for both the orthosteric and the predicted allosteric site against a curated database of human tested molecules. Considering the binding affinity and predicted blood‐brain barrier permeability and gastrointestinal absorption, we selected atovaquone and piperaquine as orthosteric and allosteric PCs. The PCs were evaluated by their capacity to bind NAGLU and the ability to restore the enzymatic activity in human MPS IIIB fibroblasts These results represent novel PCs described for MPS IIIB and demonstrate the potential to develop novel therapeutic alternatives for this and other protein deficiency diseases

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Section: Discussionmentioning

confidence: 99%

“…Conversely, Meijer et al. reported failed high‐throughput screening of pharmacological chaperones for MPS IIIB [21] . This negative result could be related to the mutation (p.S612G) present in the fibroblasts used for screening, which could be a non‐chaperone‐responsive mutation.…”

Section: Introductionmentioning

confidence: 99%

Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB

Losada,

Triana,

Vanegas

et al. 2024

ChemBioChem

View full text Add to dashboard Cite

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Iminosugar C‐Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

Zhu

Jagadeesh

Trần

et al. 2021

Chemistry A European J

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Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α‐N‐acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three‐dimensional structures of two modest homoiminosugar‐based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C‐glycosides mimicking N‐acetyl‐D‐glucosamine and bearing various pseudo‐anomeric substituents of both α‐ and β‐configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non‐functionalized and wrongly configured β‐homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

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Enzyme enhancement therapeutics for lysosomal storage diseases: Current status and perspective

Thomas

Kermode

2019

Molecular Genetics and Metabolism

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High-Throughput Screen Fails to Identify Compounds That Enhance Residual Enzyme Activity of Mutant N-Acetyl-α-Glucosaminidase in Mucopolysaccharidosis Type IIIB

Cited by 3 publications

References 25 publications

Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB

Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB

Iminosugar C‐Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

Enzyme enhancement therapeutics for lysosomal storage diseases: Current status and perspective

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