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Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria.

ABSTRACT: Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000 pharmacological agents and identified 4 compounds (I-IV) that enhanced the thermal stability of PAH and did not show substantial inhibition of PAH activity. In further studies, compounds III (3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one) and IV (5,6-dimethyl-3-(4-methyl-2-pyridinyl)-2-thioxo-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one) stabilized the functional tetrameric conformation of recombinant WT-PAH and PKU mutants. These compounds also significantly increased activity and steady-state PAH protein levels in cells transiently transfected with either WT-PAH or PKU mutants. Furthermore, PAH activity in mouse liver increased after a 12-day oral administration of low doses of compounds III and IV. Thus, we have identified 2 small molecules that may represent promising alternatives in the treatment of PKU.

SUBMITTER: Pey AL

PROVIDER: S-EPMC2441854 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria.

Pey Angel L AL Ying Ming M Cremades Nunilo N Velazquez-Campoy Adrian A Scherer Tanja T Thöny Beat B Sancho Javier J Martinez Aurora A

The Journal of clinical investigation 20080801 8

Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000 pharmacol ...[more]

PMID: 18596920

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Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria.

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Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria.

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