title: Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG.
abstract: The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low-molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2. This exercise identified eight compounds that increased the thermal stability of PMM2. Of these, four compounds functioned as potential PCs that significantly increased the stability of several destabilizing and oligomerization mutants and also increased PMM activity in a disease model of cells overexpressing PMM2 mutations. Structural analysis revealed one of these compounds to provide an excellent starting point for chemical optimization since it passed tests based on a number of pharmacochemical quality filters. The present results provide the first proof-of-concept of a possible treatment for PMM2-CDG and describe a promising chemical structure as a starting point for the development of new therapeutic agents for this severe orphan disease.
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Patricia
authors: P
authors: Yuste-Checa
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Sandra
authors: S
authors: Brasil
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Alejandra
authors: A
authors: Gámez
authors: Department of Biomedicine and KG Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors: Jarl
authors: J
authors: Underhaug
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Lourdes R
authors: LR
authors: Desviat
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Magdalena
authors: M
authors: Ugarte
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Celia
authors: C
authors: Pérez-Cerdá
authors: Department of Biomedicine and KG Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors: Aurora
authors: A
authors: Martinez
authors: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
authors: Belén
authors: B
authors: Pérez
mesh_terms: D000483:Alleles; D018981:Congenital Disorders of Glycosylation / Q000188:drug therapy / Q000235:genetics*; D055808:Drug Discovery; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D000073658:Loss of Function Mutation; D058990:Molecular Targeted Therapy; D009154:Mutation; D017875:Phosphotransferases (Phosphomutases) / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification; D055550:Protein Stability; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; D017875:Phosphotransferases (Phosphomutases); C519582:phosphomannomutase 2, human
keywords: CDG; PMM2; misfolding proteins; pharmacological chaperones