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This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring GBA1 mutations. Among these, compound 3 emerged as a lead candidate, demonstrating the ability to enhance GCase protein levels and enzymatic activity while effectively reducing the accumulation of toxic substrates in neuronal models. Importantly, pharmacokinetic studies revealed that compound 3 has favorable brain penetration, indicating its potential as a disease-modifying therapy for GBA1-related disorders affecting the central nervous system. This research not only offers a framework for developing allosteric GCase modulators but also unveils promising new therapeutic strategies for managing Gaucher disease and Parkinson\u2019s disease. The ability of compound 3 to cross the blood-brain barrier emphasizes its potential significance in addressing neurological symptoms associated with these conditions.<\/jats:p>","DOI":"10.3390\/ijms26010009","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T04:45:49Z","timestamp":1735015549000},"page":"9","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Developing Allosteric Chaperones for GBA1-Associated Disorders\u2014An Integrated Computational and Experimental Approach"],"prefix":"10.3390","volume":"26","author":[{"given":"Marta","family":"Montpeyo","sequence":"first","affiliation":[{"name":"Neurodegenerative Diseases Research Group, Vall d\u2019Hebron Research Institute (VHIR)\u2014Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e0lia","family":"P\u00e9rez-Carmona","sequence":"additional","affiliation":[{"name":"Gain Therapeutics Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-6670","authenticated-orcid":false,"given":"Elena","family":"Cubero","sequence":"additional","affiliation":[{"name":"Gain Therapeutics Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2793-1545","authenticated-orcid":false,"given":"Aida","family":"Delgado","sequence":"additional","affiliation":[{"name":"Gain Therapeutics Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ruano","sequence":"additional","affiliation":[{"name":"Gain Therapeutics Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jokin","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Gain Therapeutics Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manolo","family":"Bellotto","sequence":"additional","affiliation":[{"name":"GT Gain Therapeutics SA, 6900 Lugano, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7053-2625","authenticated-orcid":false,"given":"Marta","family":"Martinez-Vicente","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Group, Vall d\u2019Hebron Research Institute (VHIR)\u2014Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9582-7429","authenticated-orcid":false,"given":"Ana Maria","family":"Garcia-Collazo","sequence":"additional","affiliation":[{"name":"Gain Therapeutics Sucursal en Espa\u00f1a, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Smith, L., and Schapira, A.H.V. (2022). GBA variants and Parkinson disease: Mechanisms and treatments. Cells, 11.","DOI":"10.3390\/cells11081261"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Stirnemann, J., Belmatoug, N., Camou, F., Serratrice, C., Froissart, R., Caillaud, C., Levade, T., Astudillo, L., Serratrice, J., and Brassier, A. (2017). A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020441"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/10245332.2016.1240391","article-title":"Gaucher disease epidemiology and natural history: A comprehensive review of the literature","volume":"22","author":"Nalysnyk","year":"2017","journal-title":"Hematology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Boer, D.E.C., van Smeden, J., Bouwstra, J.A., and Aerts, J. (2020). Glucocerebrosidase: Functions in and beyond the lysosome. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030736"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rolfs, A., Giese, A.-K., Grittner, U., Mascher, D., Elstein, D., Zimran, A., B\u00f6ttcher, T., Lukas, J., H\u00fcbner, R., and G\u00f6lnitz, U. (2013). Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of gaucher disease patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079732"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/ajh.24491","article-title":"Glucosylsphingosine is a key biomarker of Gaucher disease","volume":"91","author":"Murugesan","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e118","DOI":"10.1182\/blood-2011-05-352971","article-title":"Elevated plasma glucosylsphingosine in Gaucher disease: Relation to phenotype, storage cell markers, and therapeutic response","volume":"118","author":"Dekker","year":"2011","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1093\/brain\/awp044","article-title":"Glucocerebrosidase mutations in clinical and pathologically proven Parkinson\u2019s disease","volume":"132","author":"Neumann","year":"2009","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1212\/WNL.0b013e3181b28601","article-title":"Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset","volume":"73","author":"Sidransky","year":"2009","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/mds.27583","article-title":"Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine","volume":"34","author":"Blandini","year":"2019","journal-title":"Mov. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Granek, Z., Barczuk, J., Siwecka, N., Rozp\u0119dek-Kami\u0144ska, W., Kucharska, E., and Majsterek, I. (2023). GBA1 gene mutations in \u03b1-synucleinopathies-molecular mechanisms underlying pathology and their clinical significance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032044"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1310\/hpj5107-553","article-title":"Enzyme replacement or substrate reduction? A review of Gaucher disease treatment options","volume":"51","author":"Holsopple","year":"2016","journal-title":"Hosp. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Beutler, E. (2004). Enzyme replacement in Gaucher disease. PLoS Med., 1.","DOI":"10.1371\/journal.pmed.0010021"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Coutinho, M.F., Santos, J.I., and Alves, S. (2016). Less is more: Substrate reduction therapy for lysosomal storage disorders. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071065"},{"key":"ref_16","first-page":"CD010324","article-title":"Enzyme replacement and substrate reduction therapy for Gaucher disease","volume":"3","author":"Shemesh","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4962","DOI":"10.1111\/j.1742-4658.2007.06041.x","article-title":"Active-site-specific chaperone therapy for Fabry disease","volume":"274","author":"Fan","year":"2007","journal-title":"FEBS J."},{"key":"ref_18","first-page":"S111","article-title":"Pharmacological chaperone therapy by active-site-specific chaperones in Fabry disease: In vitro and preclinical studies","volume":"47","author":"Germain","year":"2009","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Weber, P., Thonhofer, M., Averill, S., Davies, G.J., Santana, A.G., M\u00fcller, P., Nasseri, S.A., Offen, W.A., Pabst, B.M., and Paschke, E. (2020). Mechanistic insights into the chaperoning of human lysosomal-galactosidase activity: Highly functionalized aminocyclopentanes and C-5a-substituted derivatives of 4-epi-isofagomine. Molecules, 25.","DOI":"10.3390\/molecules25174025"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rudinskiy, M., Pons-Vizcarra, M., Sold\u00e0, T., Fregno, I., Bergmann, T.J., Ruano, A., Delgado, A., Morales, S., Barril, X., and Bellotto, M. (2023). Validation of a highly sensitive HaloTag-based assay to evaluate the potency of a novel class of allosteric \u03b2-Galactosidase correctors. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0294437"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cubero, E., Ruano, A., Delgado, A., Barril, X., Morales, S., Trapero, A., Leoni, L., Bellotto, M., Maj, R., and Guzm\u00e1n, B.C.-F. (2024). Discovery of allosteric regulators with clinical potential to stabilize alpha-L-iduronidase in mucopolysaccharidosis type I. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0303789"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1111\/j.1467-7652.2007.00263.x","article-title":"Production of glucocerebrosidase with terminal mannose glycans for enzyme replacement therapy of Gaucher\u2019s disease using a plant cell system","volume":"5","author":"Shaaltiel","year":"2007","journal-title":"Plant Biotechnol. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1021\/jm801385d","article-title":"Binding site detection and druggability index from first principles","volume":"52","author":"Seco","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_24","unstructured":"Barril, X., Alvarez-Garcia, D., and Schmidtke, P. (2013). Method of Binding Site and Binding Energy Determination by Mixed Explicit Solvent Simulations. (WO2013092922A2), Patent, Available online: https:\/\/patentimages.storage.googleapis.com\/77\/0b\/d3\/ffef95960db6fe\/WO2013092922A2.pdf."},{"key":"ref_25","first-page":"62","article-title":"Extracting atomic contributions to binding free energy using molecular dynamics simulations with mixed solvents (MDmix)","volume":"19","author":"Schmidtke","year":"2022","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Alvarez-Garcia, D., Seco, J., Schmidtke, P., and Barril, X. (2012). Druggability prediction. Protein-Ligand Interactions, Wiley-VCH.","DOI":"10.1002\/9783527645947.ch13"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8530","DOI":"10.1021\/jm5010418","article-title":"Molecular simulations with solvent competition quantify water displaceability and provide accurate interaction maps of protein binding sites","volume":"57","author":"Barril","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ruiz-Carmona, S., Alvarez-Garcia, D., Foloppe, N., Garmendia-Doval, A.B., Juhos, S., Schmidtke, P., Barril, X., Hubbard, R.E., and Morley, S.D. (2014). rDock: A fast, versatile and open source program for docking ligands to proteins and nucleic acids. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003571"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.bbadis.2007.02.003","article-title":"Enzyme enhancement activity of N-octyl-beta-valienamine on beta-glucosidase mutants associated with Gaucher disease","volume":"1772","author":"Lei","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1146\/annurev.biophys.26.1.541","article-title":"Use of surface plasmon resonance to probe the equilibrium and dynamic aspects of interactions between biological macromolecules","volume":"26","author":"Schuck","year":"1997","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/j.neuroscience.2006.01.064","article-title":"Molecular identification of an N-type Ca2+ channel in saccular hair cells","volume":"139","author":"Ramakrishnan","year":"2006","journal-title":"Neuroscience"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1002\/mds.27119","article-title":"N370S-GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson\u2019s disease","volume":"32","author":"Orgaz","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1093\/hmg\/ddw185","article-title":"Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: Relevance to Parkinson disease","volume":"25","author":"Magalhaes","year":"2016","journal-title":"Hum. Mol. Gen."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.12688\/f1000research.12090.1","article-title":"Dermal fibroblasts from patients with Parkinson\u2019s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations","volume":"6","author":"Collins","year":"2017","journal-title":"F1000Research"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Galvagnion, C., Cerri, S., Schapira, A.H.V., Blandini, F., and Di Monte, D.A. (2020). Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote \u03b1-synuclein aggregation. bioRxiv.","DOI":"10.1101\/2020.11.09.375048"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12875","DOI":"10.1021\/acs.analchem.4c02654","article-title":"Evaluation of a liquid chromatography-tandem mass spectrometry method for the analysis of glucosylceramide and galactosylceramide isoforms in cerebrospinal fluid of Parkinson\u2019s disease patients","volume":"96","author":"Pozo","year":"2024","journal-title":"Anal. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41531-022-00397-6","article-title":"Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology","volume":"8","author":"Riera","year":"2022","journal-title":"NPJ Parkinson\u2019s Dis."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Filograna, R., Civiero, L., Ferrari, V., Codolo, G., Greggio, E., Bubacco, L., Beltramini, M., and Bisaglia, M. (2015). Analysis of the catecholaminergic phenotype in human SH-SY5Y and BE(2)-M17 neuroblastoma cell lines upon differentiation. 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