000170476 001__ 170476
000170476 005__ 20260422085545.0
000170476 0247_ $$2doi$$a10.1016/j.biopha.2026.119371
000170476 0248_ $$2sideral$$a148982
000170476 037__ $$aART-2026-148982
000170476 041__ $$aeng
000170476 100__ $$0(orcid)0000-0003-4358-9110$$aConde-Giménez, María
000170476 245__ $$aVariant-dependent pharmacological rescue of phenylalanine hydroxylase supports a precision therapeutic strategy for phenylketonuria
000170476 260__ $$c2026
000170476 5060_ $$aAccess copy available to the general public$$fUnrestricted
000170476 5203_ $$aPhenylketonuria (PKU) is an inherited metabolic disorder caused by pathogenic variants in phenylalanine hydroxylase (PAH), leading to toxic phenylalanine accumulation and severe neurological complications if untreated. Current pharmacological treatment relies on tetrahydrobiopterin (BH4), which benefits only a subset of patients, highlighting a major unmet need for alternative therapies. Here, we combined high-throughput screening, computational modelling, and drug repurposing to identify pharmacological chaperones capable of rescuing PAH function. We evaluated 26 structurally diverse small molecules in HEK293T cells expressing wild-type PAH or one of eight PKU-associated variants spanning phenotypes from mild to classical disease. Chaperoning efficacy was strongly variant-dependent, and for every variant tested at least one compound produced a greater activity increase than BH4 under identical assay conditions. Notably, belinostat, a clinically approved histone deacetylase inhibitor, emerged as the most effective compound for several clinically severe variants. Mechanistically, functional rescue consistently correlated with an increased population of tetrameric, catalytically competent PAH, as quantified by mass photometry. The crystal structure of the PAH–belinostat complex (PDB ID: 9T1O), together with structural models for all compounds, provide a framework for rational optimization. These results establish a preclinical proof-of-concept for genotype-guided pharmacological chaperone therapy in PKU and support the feasibility of personalized, variant-specific treatment strategies.
000170476 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E45-20R$$9info:eu-repo/grantAgreement/ES/DGA/E45-23R$$9info:eu-repo/grantAgreement/EC/H2020/101004806/EU/MOlecular-Scale Biophysics Research Infrastructure/MOSBRI$$9This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 101004806-MOSBRI$$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-107293GB-I00$$9info:eu-repo/grantAgreement/ES/MICINN/PID2022-141068NB-I00
000170476 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
000170476 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000170476 700__ $$0(orcid)0000-0003-0195-5434$$aSalillas, Sandra
000170476 700__ $$0(orcid)0000-0002-2043-4864$$aGaliana-Cameo, María
000170476 700__ $$0(orcid)0000-0002-8784-7735$$aMartínez-Oliván, Juan E.
000170476 700__ $$0(orcid)0000-0002-8839-6796$$aMahía, Alejandro
000170476 700__ $$aLedesma, Manuel
000170476 700__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos, Juan José
000170476 700__ $$0(orcid)0000-0003-4058-2888$$aMaity, Ritwik
000170476 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez-Campoy, Adrián$$uUniversidad de Zaragoza
000170476 700__ $$aDíaz-de-Villegas, María D.
000170476 700__ $$0(orcid)0000-0002-3122-9401$$aHurtado-Guerrero, Ramón
000170476 700__ $$aSancho, Javier
000170476 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000170476 773__ $$g199 (2026), 119371 [15 pp.]$$pBiomed. pharmacother.$$tBIOMEDICINE & PHARMACOTHERAPY$$x0753-3322
000170476 8564_ $$s8365144$$uhttps://zaguan.unizar.es/record/170476/files/texto_completo.pdf$$yVersión publicada
000170476 8564_ $$s2409289$$uhttps://zaguan.unizar.es/record/170476/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000170476 909CO $$ooai:zaguan.unizar.es:170476$$particulos$$pdriver
000170476 951__ $$a2026-04-22-08:33:14
000170476 980__ $$aARTICLE