ArticleHuman molecular genetics2013
Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 38 citations in OpenAlex.
- Novel Treatment Strategy for Patients With Urea Cycle Disorders: Pharmacological Chaperones Enhance Enzyme Stability and Activity in Patient-Derived Liver Disease Models.Journal of inherited metabolic disease · 2025Article
- Galactosemia: Towards Pharmacological Chaperones.Journal of personalized medicine · 2021Review
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- A Pharmacological Chaperone Therapy for Acute Intermittent Porphyria.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- β-Glucose-1,6-Bisphosphate Stabilizes Pathological Phophomannomutase2 Mutants In Vitro and Represents a Lead Compound to Develop Pharmacological Chaperones for the Most Common Disorder of Glycosylation, PMM2-CDG.International journal of molecular sciences · 2019Article
- An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.Nature chemical biology · 2019Article
- EU-OPENSCREEN: A Novel Collaborative Approach to Facilitate Chemical Biology.SLAS discovery : advancing life sciences R & D · 2019Article
- Conformational stabilization as a strategy to prevent nucleophosmin mislocalization in leukemia.Scientific reports · 2017Article
- From structural biology to designing therapy for inborn errors of metabolism.Journal of inherited metabolic disease · 2016Review
- Compromised catalysis and potential folding defects in in vitro studies of missense mutants associated with hereditary phosphoglucomutase 1 deficiency.The Journal of biological chemistry · 2014Article
- Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia.Orphanet journal of rare diseases · 2014Review
- Chaperoning G protein-coupled receptors: from cell biology to therapeutics.Endocrine reviews · 2014Review
- Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators.Journal of inherited metabolic disease · 2014Review
- Emerging novel concept of chaperone therapies for protein misfolding diseases.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2014Review
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some residual ATR activity. The aim of the present study was to seek pharmacological chaperones as a tailored therapy for stabilizing the ATR protein. High-throughput ligand screening of over 2000 compounds was performed; six were found to enhance the thermal stability of purified recombinant ATR. Further studies using a well-established bacterial system in which the recombinant ATR protein was expressed in the presence of these six compounds, showed them all to increase the stability of the wild-type ATR and the p.Ile96Thr mutant proteins. Compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) significantly increased this stability and did not act as an inhibitor of the purified protein. Importantly, compound V increased the activity of ATR in patient-derived fibroblasts harboring the destabilizing p.Ile96Thr mutation in a hemizygous state to within control range. When cobalamin was coadministrated with compound V, mutant ATR activity further improved. Oral administration of low doses of compound V to C57BL/6J mice for 12 days, led to increase in steady-state levels of ATR protein in liver and brain (disease-relevant organs). These results hold promise for the clinical use of pharmacological chaperones in MMA cblB type patients harboring chaperone-responsive mutations.
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