Novel pharmacological chaperones that correct phenylketonuria in mice

Phenylketonuria (PKU) is caused by inherited phenylalanine-hydroxylase (PAH) deficiency and, in many genotypes, it is associated with protein misfolding. The natural cofactor of PAH, tetrahydrobiopterin (BH(4)), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH(4)...

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Bibliographic Details
Published in:Human molecular genetics 2012-04, Vol.21 (8), p.1877-1887
Main Authors: SANTOS-SIERRA, Sandra, KIRCHMAIR, Johannes, LAGLER, Florian B, PERNA, Anna M, REISS, Dunja, KEMTER, Kristina, RÖSCHINGER, Wulf, GLOSSMANN, Hartmut, GERSTING, Soren W, MUNTAU, Ania C, WOLBER, Gerhard
Format: Article
Language:English
Subjects:
Aminoacid disorders
Animals
Binding Sites
Biological and medical sciences
Biopterins - analogs & derivatives
Biopterins - metabolism
Blood
Catalytic Domain
Cell Line, Tumor
Cell Survival - drug effects
Chaperones
Cofactors
Drug Discovery
Drug Evaluation, Preclinical
Drugs
Enzymatic activity
Enzyme Stability
Errors of metabolism
Fundamental and applied biological sciences. Psychology
Genetics of eukaryotes. Biological and molecular evolution
Genotypes
Humans
Hydantoins - chemistry
Hydantoins - metabolism
Hydantoins - pharmacology
Hydantoins - toxicity
Medical sciences
Metabolic diseases
Mice
Molecular and cellular biology
Oxidation
Oxidation-Reduction
Phenylalanine - metabolism
Phenylalanine Hydroxylase - chemistry
Phenylalanine Hydroxylase - deficiency
Phenylalanine Hydroxylase - genetics
Phenylalanine Hydroxylase - metabolism
Phenylketonuria
Phenylketonurias - drug therapy
Phenylketonurias - metabolism
Protein Folding
Proteolysis
Small Molecule Libraries
tetrahydrobiopterin
Uracil - analogs & derivatives
Uracil - chemistry
Uracil - metabolism
Uracil - pharmacology
Uracil - toxicity
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Summary:Phenylketonuria (PKU) is caused by inherited phenylalanine-hydroxylase (PAH) deficiency and, in many genotypes, it is associated with protein misfolding. The natural cofactor of PAH, tetrahydrobiopterin (BH(4)), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH(4) shows limited efficacy in some PKU genotypes and its chemical synthesis is very costly. Taking an integrated drug discovery approach which has not been applied to this target before, we identified alternative PCs for the treatment of PKU. Shape-focused virtual screening of the National Cancer Institute's chemical library identified 84 candidate molecules with potential to bind to the active site of PAH. An in vitro evaluation of these yielded six compounds that restored the enzymatic activity of the unstable PAHV106A variant and increased its stability in cell-based assays against proteolytic degradation. During a 3-day treatment study, two compounds (benzylhydantoin and 6-amino-5-(benzylamino)-uracil) substantially improved the in vivo Phe oxidation and blood Phe concentrations of PKU mice (Pah(enu1)). Notably, benzylhydantoin was twice as effective as tetrahydrobiopterin. In conclusion, we identified two PCs with high in vivo efficacy that may be further developed into a more effective drug treatment of PKU.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/dds001