ArticleJournal of medicinal chemistry2022
Identification of Human Alanine-Glyoxylate Aminotransferase Ligands as Pharmacological Chaperones for Variants Associated with Primary Hyperoxaluria Type 1.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 12 citations in OpenAlex.
- Opportunities in Primary and Enteric Hyperoxaluria at the Cross-Roads Between the Clinic and Laboratory.Kidney international reports · 2024Article
- Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor.ACS medicinal chemistry letters · 2024Article
- Molecular Mechanisms, Genotype-Phenotype Correlations and Patient-Specific Treatments in Inherited Metabolic Diseases.Journal of personalized medicine · 2023Article
- Searching glycolate oxidase inhibitors based on QSAR, molecular docking, and molecular dynamic simulation approaches.Scientific reports · 2022Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Primary hyperoxaluria type I (PH1) is a rare kidney disease due to the deficit of alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5'-phosphate-dependent enzyme responsible for liver glyoxylate detoxification, which in turn prevents oxalate formation and precipitation as kidney stones. Many PH1-associated missense mutations cause AGT misfolding. Therefore, the use of pharmacological chaperones (PCs), small molecules that promote correct folding, represents a useful therapeutic option. To identify ligands acting as PCs for AGT, we first performed a small screening of commercially available compounds. We tested each molecule by a dual approach aimed at defining the inhibition potency on purified proteins and the chaperone activity in cells expressing a misfolded variant associated with PH1. We then performed a chemical optimization campaign and tested the resulting synthetic molecules using the same approach. Overall, the results allowed us to identify a promising hit compound for AGT and draw conclusions about the requirements for optimal PC activity.
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Registered trials
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