Identification and development of new pharmacological chaperones for phenylketonuria

Abstract

Resumen del póster presentado a la VII National Conference of the Institute for Biocomputation and Physics of Complex Systems (BIFI), celebrada en Zaragoza (España) del 4 al 6 de febrero de 2015.Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutations of phenylalanine hydroxylase (PAH) gene. Nowadays, more than 550 disease-causing PAH mutations have been identified and most of them induce loss of conformational stability and decreased physiological enzymatic activity. Currently, one of the most promising molecular approaches to treat this disease involves using small molecules known as pharmacological chaperones that bind to the native state of the unstable enzyme rescuing its physiological function. Actually, BH4, the natural cofactor of PAH, is administered for the management of some PKU patients and it is believed that it acts through that mechanism. Despite this fact, BH4 is only effective for some forms of mild PKU so that we propose to find novel PKU chaperones unrelated to BH4. A previous work of this group identified two such compounds that enhanced the thermal stability of the WT enzyme and solved the X-ray structure of the complex between the enzyme and one of the chaperones. Based on these findings, we are synthetizing a group of novel compounds and testing their effect on thermal denaturation assays. Concurrently, we are testing over 10,000 chemical compounds of a commercial diversity chemical library by applying a high-throughput screening method. These new compounds may represent promising pharmacological entities for non BH4 responsive PKU patients.Peer Reviewe