Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase.

ABSTRACT: Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chap

SUBMITTER: Conde-Gimenez M 

PROVIDER: S-EPMC9100405 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature