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Sandra Santos-Sierra, Johannes Kirchmair, Anna M. Perna, Dunja Reiß, Kristina Kemter, Wulf Röschinger, Hartmut Glossmann, Søren W. Gersting, Ania C. Muntau, Gerhard Wolber, Florian B. Lagler, Novel pharmacological chaperones that correct phenylketonuria in mice, Human Molecular Genetics, Volume 21, Issue 8, 15 April 2012, Pages 1877–1887, https://doi.org/10.1093/hmg/dds001
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Abstract
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 (BH4), can act as a pharmacological chaperone (PC) that rescues enzyme function. However, BH4 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 (Pahenu1). 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.
- oxidation
- cancer
- genotype
- libraries
- molecular chaperones
- phenylalanine
- phenylalanine hydroxylase
- phenylketonurias
- portacaval shunt, surgical
- uracil
- enzymes
- mice
- pharmacology
- proteolysis
- drug discovery
- sapropterin
- precordial catch syndrome
- binding (molecular function)
- catabolism
- molecule
- photon correlation spectroscopy