title: Fluphenazine·HCl and Epigallocatechin Gallate Modulate the Rate of Formation and Structural Properties of Apolipoprotein C-II Amyloid Fibrils.
abstract: Protein misfolding and aggregation, leading to amyloid fibril formation, are characteristic of many devastating and debilitating amyloid diseases. Accordingly, there is significant interest in the mechanisms underlying amyloid fibril formation and identification of possible intervention tools. Small molecule drug compounds approved for human use or for use in phase I-III clinical trials were investigated for their effects on amyloid formation by human apolipoprotein (apo) C-II. Several of these compounds modulated the rate of amyloid formation by apoC-II. Epigallocatechin gallate (EGCG), a green tea catechin, was an effective inhibitor of apoC-II fibril formation, and the antipsychotic drug, fluphenazine·HCl, was a potent activator. Both EGCG and fluphenazine·HCl exerted concentration-dependent effects on the rate of fibril formation, bound to apoC-II fibrils with high affinity, and competitively reduced thioflavin T binding. EGCG significantly altered the size distribution of fibrils, most likely by promoting the lateral association of fibrils and subsequent formation of large aggregates. Fluphenazine·HCl did not significantly alter the size distribution of fibrils, but it may induce the formation of a small population of rod-like fibrils that differ from the characteristic ribbon-like fibrils normally observed for apoC-II. The findings of this study emphasize the effects of small molecule drugs on the kinetics of amyloid fibril formation and their roles in determining fibril structure and aggregate size.
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Courtney O
authors.initials: CO
authors.lastname: Zlatic
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mao
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Ryan
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Yee-Foong
authors.initials: YF
authors.lastname: Mok
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Blaine R
authors.initials: BR
authors.lastname: Roberts
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Howlett
authors.affiliation: †Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, ‡The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Michael D W
authors.initials: MD
authors.lastname: Griffin
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D053304:Apolipoprotein C-II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D052160:Benzothiazoles; D001667:Binding, Competitive; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D055808:Drug Discovery; D015507:Drugs, Investigational / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D005476:Fluphenazine / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010316:Particle Size; D066329:Protein Aggregates / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D054852:Small Molecule Libraries; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000378:metabolism; D014461:Ultracentrifugation
chemical_list: D000682:Amyloid; D014150:Antipsychotic Agents; D053304:Apolipoprotein C-II; D052160:Benzothiazoles; D015507:Drugs, Investigational; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013844:Thiazoles; C009462:thioflavin T; D002392:Catechin; C045651:epigallocatechin gallate; D005476:Fluphenazine