{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:25:22Z","timestamp":1772252722587,"version":"3.50.1"},"reference-count":72,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T00:00:00Z","timestamp":1703808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Parma"},{"name":"Polytechnic University of Marche, Italy"},{"name":"Italian Ministry of Instruction, University and Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinson\u2019s disease that has been repurposed as a TTR stabiliser. We characterised 3-O-methyltolcapone and two newly synthesized lipophilic analogues, which are expected to be protected from the metabolic glucuronidation that is responsible for the lability of tolcapone in the organism. Immunoblotting assays indicated the high degree of TTR stabilisation, coupled with binding selectivity towards TTR in diluted plasma of 3-O-methyltolcapone and its lipophilic analogues. Furthermore, in vitro toxicity data showed their several-fold improved neuronal and hepatic safety compared to tolcapone. Calorimetric and structural data showed that both T4 binding sites of TTR are occupied by 3-O-methyltolcapone and its lipophilic analogs, consistent with an effective TTR tetramer stabilisation. Moreover, in vitro permeability studies showed that the three compounds can effectively cross the blood-brain barrier, which is a prerequisite for the inhibition of TTR amyloidogenesis in the cerebrospinal fluid. Our data demonstrate the relevance of 3-O-methyltolcapone and its lipophilic analogs as potent inhibitors of TTR amyloidogenesis.<\/jats:p>","DOI":"10.3390\/ijms25010479","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T09:15:11Z","timestamp":1703841311000},"page":"479","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-6396","authenticated-orcid":false,"given":"Thanalai","family":"Poonsiri","sequence":"first","affiliation":[{"name":"Bioorganic Chemistry and Bio-Crystallography Laboratory (B<sub>2<\/sub>Cl), Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano, 39100 Bolzano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-2038","authenticated-orcid":false,"given":"Davide","family":"Dell\u2019Accantera","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17\/a, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5715-9993","authenticated-orcid":false,"given":"Valentina","family":"Loconte","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA"},{"name":"Lawrence Berkeley National Laboratory, Molecular Biophysics and Integrated Bioimaging Division, Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9993-3262","authenticated-orcid":false,"given":"Alessandro","family":"Casnati","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17\/a, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Cervoni","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences, University of Rome \u201cLa Sapienza\u201d, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8384-4844","authenticated-orcid":false,"given":"Alessandro","family":"Arcovito","sequence":"additional","affiliation":[{"name":"Department of Biotechnological Sciences and Intensive Care, Catholic University of Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli\u2014IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6299-888X","authenticated-orcid":false,"given":"Stefano","family":"Benini","sequence":"additional","affiliation":[{"name":"Bioorganic Chemistry and Bio-Crystallography Laboratory (B<sub>2<\/sub>Cl), Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano, 39100 Bolzano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8092-4638","authenticated-orcid":false,"given":"Marco","family":"Cipolloni","sequence":"additional","affiliation":[{"name":"TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Cacioni","sequence":"additional","affiliation":[{"name":"TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"De Franco","sequence":"additional","affiliation":[{"name":"TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4810-3960","authenticated-orcid":false,"given":"Nicola","family":"Giacch\u00e8","sequence":"additional","affiliation":[{"name":"TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0682-023X","authenticated-orcid":false,"given":"Serena","family":"Rinaldo","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences, University of Rome \u201cLa Sapienza\u201d, P.le Aldo Moro 5, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7187-0180","authenticated-orcid":false,"given":"Claudia","family":"Folli","sequence":"additional","affiliation":[{"name":"Department of Food and Drug, University of Parma, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-9865","authenticated-orcid":false,"given":"Francesco","family":"Sansone","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17\/a, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolfo","family":"Berni","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17\/a, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5607-6061","authenticated-orcid":false,"given":"Michele","family":"Cianci","sequence":"additional","affiliation":[{"name":"Department of Agricultural, Food and Environmental Sciences, Universit\u00e0 Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0083-6729(04)69010-8","article-title":"Plasma Retinol-Binding Protein: Structure and Interactions with Retinol, Retinoids, and Transthyretin","volume":"69","author":"Zanotti","year":"2004","journal-title":"Vitam. Horm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1107\/S0907444996003046","article-title":"Structures of Human Transthyretin Complexed with Thyroxine at 2.0 \u00c5 Resolution and 3\u2032,5\u2032-Dinitro-N-Acetyl-L-Thyronine at 2.2 \u00c5 Resolution","volume":"52","author":"Wojtczak","year":"1996","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"25832","DOI":"10.1074\/jbc.M109.017657","article-title":"Amyloidogenic Potential of Transthyretin Variants","volume":"284","author":"Cendron","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1042\/CS20160413","article-title":"Transthyretin Amyloidosis: An under-Recognized Neuropathy and Cardiomyopathy","volume":"131","author":"Galant","year":"2017","journal-title":"Clin. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e01371","DOI":"10.1002\/brb3.1371","article-title":"Advances in the Treatment of Hereditary Transthyretin Amyloidosis: A Review","volume":"9","author":"Gertz","year":"2019","journal-title":"Brain Behav."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.sbi.2009.12.009","article-title":"Structure-Based Design of Kinetic Stabilizers That Ameliorate the Transthyretin Amyloidoses","volume":"20","author":"Connelly","year":"2010","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5008","DOI":"10.1038\/s41467-019-13038-z","article-title":"Cryo-EM Structure of a Transthyretin-Derived Amyloid Fibril from a Patient with Hereditary ATTR Amyloidosis","volume":"10","author":"Schmidt","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1107\/S2052252514021113","article-title":"Binding Site Asymmetry in Human Transthyretin: Insights from a Joint Neutron and X-ray Crystallographic Analysis Using Perdeuterated Protein","volume":"1","author":"Haupt","year":"2014","journal-title":"IUCrJ"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1038\/s41467-019-08609-z","article-title":"A Molecular Mechanism for Transthyretin Amyloidogenesis","volume":"10","author":"Yee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2217\/nmt-2018-0033","article-title":"Patisiran, an RNAi Therapeutic for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis","volume":"9","author":"Kristen","year":"2019","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1056\/NEJMe1805499","article-title":"Oligonucleotide Drugs for Transthyretin Amyloidosis","volume":"379","author":"Buxbaum","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9629","DOI":"10.1073\/pnas.1121005109","article-title":"Tafamidis, a Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade","volume":"109","author":"Bulawa","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9992","DOI":"10.1073\/pnas.1300761110","article-title":"AG10 Inhibits Amyloidogenesis and Cellular Toxicity of the Familial Amyloid Cardiomyopathy-Associated V122I Transthyretin","volume":"110","author":"Penchala","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/s41598-017-00338-x","article-title":"Inhibition of the Mechano-Enzymatic Amyloidogenesis of Transthyretin: Role of Ligand Affinity, Binding Cooperativity and Occupancy of the Inner Channel","volume":"7","author":"Verona","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10787","DOI":"10.1038\/ncomms10787","article-title":"Repositioning Tolcapone as a Potent Inhibitor of Transthyretin Amyloidogenesis and Associated Cellular Toxicity","volume":"7","author":"Gallego","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29769","DOI":"10.1074\/jbc.M115.690172","article-title":"Transthyretin Binding Heterogeneity and Antiamyloidogenic Activity of Natural Polyphenols and Their Metabolites","volume":"290","author":"Florio","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16218","DOI":"10.1021\/acs.jmedchem.2c00511","article-title":"Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis","volume":"65","author":"Mizuguchi","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14673","DOI":"10.1021\/acs.jmedchem.2c01195","article-title":"Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation","volume":"65","author":"Pinheiro","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1080\/14756366.2020.1760262","article-title":"Natural Compounds as Inhibitors of Transthyretin Amyloidosis and Neuroprotective Agents: Analysis of Structural Data for Future Drug Design","volume":"35","author":"Ciccone","year":"2020","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1080\/13506129.2016.1207163","article-title":"Early Intervention with Tafamidis Provides Long-Term (5.5-Year) Delay of Neurologic Progression in Transthyretin Hereditary Amyloid Polyneuropathy","volume":"23","author":"Amass","year":"2016","journal-title":"Amyloid"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/13506129.2017.1301419","article-title":"Tafamidis Delays Disease Progression in Patients with Early Stage Transthyretin Familial Amyloid Polyneuropathy: Additional Supportive Analyses from the Pivotal Trial","volume":"24","author":"Keohane","year":"2017","journal-title":"Amyloid"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117954681773032","DOI":"10.1177\/1179546817730322","article-title":"Treatment with Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy","volume":"11","author":"Sultan","year":"2017","journal-title":"Clin. Med. Insights Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1007\/s40265-019-01129-6","article-title":"Tafamidis: A Review in Transthyretin Amyloidosis with Polyneuropathy","volume":"79","author":"Lamb","year":"2019","journal-title":"Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1185\/03007995.2012.754348","article-title":"THAOS\u2014The Transthyretin Amyloidosis Outcomes Survey: Initial Report on Clinical Manifestations in Patients with Hereditary and Wild-Type Transthyretin Amyloidosis","volume":"29","author":"Coelho","year":"2013","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1001\/jama.2013.283815","article-title":"Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial","volume":"310","author":"Berk","year":"2013","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"16427","DOI":"10.1073\/pnas.202495199","article-title":"Sequence-Dependent Denaturation Energetics: A Major Determinant in Amyloid Disease Diversity","volume":"99","author":"Jiang","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1080\/13506120600722449","article-title":"R104H May Suppress Transthyretin Amyloidogenesis by Thermodynamic Stabilization, but Not by the Kinetic Mechanism Characterizing T119 Interallelic Trans-Suppression","volume":"13","author":"Sekijima","year":"2006","journal-title":"Amyloid"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s002109900168","article-title":"Detection of Tolcapone in the Cerebrospinal Fluid of Parkinsonian Subjects","volume":"360","author":"Russ","year":"1999","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/febs.15339","article-title":"Tolcapone, a Potent Aggregation Inhibitor for the Treatment of Familial Leptomeningeal Amyloidosis","volume":"288","author":"Pinheiro","year":"2021","journal-title":"FEBS J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1136\/jnnp-2014-308107","article-title":"CNS Involvement in V30M Transthyretin Amyloidosis: Clinical, Neuropathological and Biochemical Findings","volume":"86","author":"Maia","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1136\/jnnp-2013-305973","article-title":"Changes in Pathological and Biochemical Findings of Systemic Tissue Sites in Familial Amyloid Polyneuropathy More than 10\u2005Years after Liver Transplantation","volume":"85","author":"Oshima","year":"2014","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.jns.2009.07.028","article-title":"Distinct Characteristics of Amyloid Deposits in Early- and Late-Onset Transthyretin Val30Met Familial Amyloid Polyneuropathy","volume":"287","author":"Koike","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41582-019-0210-4","article-title":"Hereditary Transthyretin Amyloidosis: A Model of Medical Progress for a Fatal Disease","volume":"15","author":"Adams","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/S0140-6736(05)61511-5","article-title":"Tolcapone and Fulminant Hepatitis","volume":"352","author":"Assal","year":"1998","journal-title":"Lancet"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1001\/archneur.57.2.263","article-title":"Tolcapone and Hepatotoxic Effects","volume":"57","author":"Olanow","year":"2000","journal-title":"Arch. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1023\/A:1005549304404","article-title":"Tolcapone-Related Fulminant Hepatitis: Electron Microscopy Shows Mitochondrial Alterations","volume":"45","author":"Spahr","year":"2000","journal-title":"Dig. Dis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1046\/j.1365-2125.1999.00036.x","article-title":"Metabolism and Excretion of Tolcapone, a Novel Inhibitor of Catechol-O-Methyltransferase","volume":"48","author":"Jorga","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_38","unstructured":"Bethesda, M.D. (2021, October 25). National Institute of Diabetes and Digestive and Kidney Diseases: Tolcapone. In LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK548573\/."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Loconte, V., Cianci, M., Menozzi, I., Sbravati, D., Sansone, F., Casnati, A., and Berni, R. (2020). Interactions of Tolcapone Analogues as Stabilizers of the Amyloidogenic Protein Transthyretin. Bioorg Chem., 103.","DOI":"10.1016\/j.bioorg.2020.104144"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1006\/jmbi.2000.4078","article-title":"A Comparative Analysis of 23 Structures of the Amyloidogenic Protein Transthyretin","volume":"302","author":"Eneqvist","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Di, L., and Kerns, E.H. (2016). Drug-Like Properties, Academic Press. [2nd ed.].","DOI":"10.1016\/B978-0-12-801076-1.00020-4"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/j.1582-4934.2008.00665.x","article-title":"Docking, Virtual High Throughput Screening and in Silico Fragment-Based Drug Design","volume":"13","author":"Zoete","year":"2009","journal-title":"J. Cell Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.ejmech.2016.08.003","article-title":"Systemic Optimization and Structural Evaluation of Quinoline Derivatives as Transthyretin Amyloidogenesis Inhibitors","volume":"123","author":"Kim","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.ejmech.2016.02.074","article-title":"A Novel Bis-Furan Scaffold for Transthyretin Stabilization and Amyloid Inhibition","volume":"121","author":"Almeida","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"113847","DOI":"10.1016\/j.ejmech.2021.113847","article-title":"Targeting Transthyretin in Alzheimer\u2019s Disease: Drug Discovery of Small-Molecule Chaperones as Disease-Modifying Drug Candidates for Alzheimer\u2019s Disease","volume":"226","author":"Cotrina","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jsb.2019.08.011","article-title":"Structure-Activity Relationships of Flurbiprofen Analogues as Stabilizers of the Amyloidogenic Protein Transthyretin","volume":"208","author":"Loconte","year":"2019","journal-title":"J. Struct. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1021\/jm0109964","article-title":"Synthesis of 1-(3,4-Dihydroxy-5-Nitrophenyl)-2-Phenyl-Ethanone and Derivatives as Potent and Long-Acting Peripheral Inhibitors of Catechol-O-Methyltransferase","volume":"45","author":"Learmonth","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3396","DOI":"10.1021\/jm1001524","article-title":"Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-Methyltransferase","volume":"53","author":"Kiss","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_49","unstructured":"Valko, K. (2014). Physicochemical and Biomimetic Properties in Drug Discovery: Chromatographic Techniques for Lead Optimization, John Wiley & Sons Inc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.neuropharm.2003.10.015","article-title":"Differences in Toxicity of the Catechol-O-Methyl Transferase Inhibitors, Tolcapone and Entacapone to Cultured Human Neuroblastoma Cells","volume":"46","author":"Korlipara","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/cam4.1065","article-title":"Tolcapone Induces Oxidative Stress Leading to Apoptosis and Inhibition of Tumor Growth in Neuroblastoma","volume":"6","author":"Maser","year":"2017","journal-title":"Cancer Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7862","DOI":"10.1021\/acs.jmedchem.8b00817","article-title":"Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis","volume":"61","author":"Miller","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6507","DOI":"10.1021\/acs.jmedchem.5b00544","article-title":"Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma","volume":"58","author":"Iakovleva","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0223-5234(03)00012-6","article-title":"High Throughput Artificial Membrane Permeability Assay for Blood\u2013Brain Barrier","volume":"38","author":"Di","year":"2003","journal-title":"Eur. J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7584","DOI":"10.1021\/acs.jmedchem.6b00666","article-title":"Development of Blood\u2013Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity","volume":"59","author":"Silva","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ijpharm.2016.01.074","article-title":"A New PAMPA Model Using an In-House Brain Lipid Extract for Screening the Blood\u2013Brain Barrier Permeability of Drug Candidates","volume":"501","author":"Bicker","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.drudis.2011.07.010","article-title":"Finding a Better Path to Drug Selectivity","volume":"16","author":"Kawasaki","year":"2011","journal-title":"Drug Discov. Today"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1006\/jmbi.2000.4415","article-title":"Transthyretin Stability as a Key Factor in Amyloidogenesis: X-ray Analysis at Atomic Resolution","volume":"306","author":"Lamzin","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1097\/NRL.0000000000000337","article-title":"Current Review of Leptomeningeal Amyloidosis Associated with Transthyretin Mutations","volume":"26","author":"Qin","year":"2021","journal-title":"Neurologist"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1007\/s00415-014-7594-2","article-title":"Oculoleptomeningeal Amyloidosis Associated with Transthyretin Leu12Pro in an African Patient","volume":"262","author":"McColgan","year":"2015","journal-title":"J. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1021\/acsmedchemlett.9b00688","article-title":"Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage","volume":"11","author":"Sinha","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1002\/jcc.21797","article-title":"Fast Docking Using the CHARMM Force Field with EADock DSS","volume":"32","author":"Grosdidier","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"W270","DOI":"10.1093\/nar\/gkr366","article-title":"SwissDock, a Protein-Small Molecule Docking Web Service Based on EADock DSS","volume":"39","author":"Grosdidier","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/jcc.20832","article-title":"FACTS: Fast Analytical Continuum Treatment of Solvation","volume":"29","author":"Caflisch","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Wang, D., Mu, Y., Dong, H., Yan, H., Hao, C., Wang, X., and Zhang, L. (2018). Chemical Constituents of the Ethyl Acetate Extract from Diaphragma Juglandis Fructus and Their Inhibitory Activity on Nitric Oxide Production In Vitro. Molecules, 23.","DOI":"10.3390\/molecules23010072"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Nilsson, L., Larsson, A., Begum, A., Iakovleva, I., Carlsson, M., Br\u00e4nnstr\u00f6m, K., Sauer-Eriksson, A.E., and Olofsson, A. (2016). Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153112"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1107\/S1600577516016465","article-title":"P13, the EMBL Macromolecular Crystallography Beamline at the Low-Emittance PETRA III Ring for High- and Low-Energy Phasing with Variable Beam Focusing","volume":"24","author":"Cianci","year":"2017","journal-title":"J. Synchrotron Radiat."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1107\/S0907444909047337","article-title":"XDS","volume":"66","author":"Kabsch","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1107\/S0907444905036693","article-title":"Scaling and Assessment of Data Quality","volume":"62","author":"Evans","year":"2006","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1107\/S0907444907037195","article-title":"MrBUMP: An Automated Pipeline for Molecular Replacement","volume":"64","author":"Keegan","year":"2008","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: A Comprehensive Python-Based System for Macromolecular Structure Solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and Development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/479\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:44:18Z","timestamp":1760132658000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,29]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25010479"],"URL":"https:\/\/doi.org\/10.3390\/ijms25010479","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.10.25.563927","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,29]]}}}