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Title: The triphenylmethane dye brilliant blue G is only moderately effective at inhibiting amyloid formation by human amylin or at disaggregating amylin amyloid fibrils, but interferes with amyloid assays; Implications for inhibitor design

Journal Article · · PLoS ONE
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The development of inhibitors of islet amyloid formation is important as pancreatic amyloid deposition contributes to type-2 diabetes and islet transplant failure. The Alzheimer’s Aβ peptide and human amylin (h-amylin), the polypeptide responsible for amyloid formation in type-2 diabetes, share common physio-chemical features and some inhibitors of Aβ also inhibit amyloid formation by h-amylin and vice versa. Thus, a popular and potentially useful strategy to find lead compounds for anti-amylin amyloid agents is to examine compounds that have effects on Aβ amyloid formation. The triphenylmethane dye, brilliant blue G (BBG, Sodium;3-[[4-[(E)-[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-N-ethyl-3-methylanilino]methyl]benzenesulfonate) has been shown to modulate Aβ amyloid formation and inhibit Aβ induced toxicity. However, the effects of BBG on h-amylin have not been examined, although other triphenylmethane derivatives inhibit h-amylin amyloid formation. The compound has only a modest impact on h-amylin amyloid formation unless it is added in significant excess. BBG also remodels preformed h-amylin amyloid fibrils if added in excess, however BBG has no significant effect on h-amylin induced toxicity towards cultured β-cells or cultured CHO-T cells except at high concentrations. BBG is shown to interfere with standard thioflavin-T assays of h-amylin amyloid formation and disaggregation, highlighting the difficulty of interpreting such experiments in the absence of other measurements. BBG also interferes with ANS based assays of h-amylin amyloid formation. The work highlights the differences between inhibition of Aβ and h-amylin amyloid formation, illustrates the limitation of using Aβ inhibitors as leads for h-amylin amyloid inhibitors, and reinforces the difficulties in interpreting dye binding assays of amyloid formation.

Research Organization:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
SC0012704
OSTI ID:
1556818
Alternate ID(s):
OSTI ID: 1689562
Report Number(s):
BNL-220180-2020-JACI; 10.1371/journal.pone.0219130
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Vol. 14 Journal Issue: 8; ISSN 1932-6203
Publisher:
Public Library of Science (PLoS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 4 works
Citation information provided by
Web of Science

References (49)

The Sulfated Triphenyl Methane Derivative Acid Fuchsin Is a Potent Inhibitor of Amyloid Formation by Human Islet Amyloid Polypeptide and Protects against the Toxic Effects of Amyloid Formation journal July 2010
Diabetes Mellitus and Dementia journal March 2014
The Amyloid State of Proteins in Human Diseases journal March 2012
Selectively N-Methylated Soluble IAPP Mimics as Potent IAPP Receptor Agonists and Nanomolar Inhibitors of Cytotoxic Self-Assembly of Both IAPP and Aβ40 journal August 2013
Insight into Clustering in Poly(ethylene oxide) Solutions journal September 2004
EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity journal April 2010
Thioflavine T interaction with synthetic Alzheimer's disease β-amyloid peptides: Detection of amyloid aggregation in solution journal March 1993
Oligomeric Amyloid-β Toxicity Can Be Inhibited by Blocking Its Cellular Binding in Cortical Neuronal Cultures with Addition of the Triphenylmethane Dye Brilliant Blue G journal April 2016
Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus journal July 2011
A Safe, Blood-Brain Barrier Permeable Triphenylmethane Dye Inhibits Amyloid-β Neurotoxicity by Generating Nontoxic Aggregates journal September 2011
The Flavanol (−)-Epigallocatechin 3-Gallate Inhibits Amyloid Formation by Islet Amyloid Polypeptide, Disaggregates Amyloid Fibrils, and Protects Cultured Cells against IAPP-Induced Toxicity journal September 2010
Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons journal September 2018
RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity journal January 2018
Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics journal May 2016
Brilliant Blue G improves cognition in an animal model of Alzheimer’s disease and inhibits amyloid-β-induced loss of filopodia and dendrite spines in hippocampal neurons journal October 2014
Molecular basis of the inhibition and disaggregation of thermally-induced amyloid fibrils of human serum albumin by an anti-Parkinson's drug, benserazide hydrochloride journal March 2019
Binding Modes of Thioflavin-T to the Single-Layer β-Sheet of the Peptide Self-Assembly Mimics journal December 2009
Using an in-vacuum CCD detector for simultaneous small- and wide-angle scattering at beamline X9 journal January 2013
Widespread Amyloid Deposition in Transplanted Human Pancreatic Islets journal August 2008
Islet amyloid: From fundamental biophysics to mechanisms of cytotoxicity journal February 2013
Influence of methionine–ruthenium complex on the fibril formation of human islet amyloid polypeptide journal January 2019
Site-Specific Fluorescence Polarization for Studying the Disaggregation of α-Synuclein Fibrils by Small Molecules journal November 2016
Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. journal June 1987
Fluorescence Quantum Yield of Thioflavin T in Rigid Isotropic Solution and Incorporated into the Amyloid Fibrils journal October 2010
The Binding of Thioflavin T and Its Neutral Analog BTA-1 to Protofibrils of the Alzheimer’s Disease Aβ16–22 Peptide Probed by Molecular Dynamics Simulations journal December 2008
Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes journal September 2010
Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology journal February 2013
Incorporation of Pseudoproline Derivatives Allows the Facile Synthesis of Human IAPP, a Highly Amyloidogenic and Aggregation-Prone Polypeptide journal January 2005
Is type 2 diabetes an amyloidosis and does it really matter (to patients)? journal March 2010
Metabolic stress, IAPP and islet amyloid journal August 2012
Seeding Specificity in Amyloid Growth Induced by Heterologous Fibrils journal January 2004
Inhibition of Glycosaminoglycan-Mediated Amyloid Formation by Islet Amyloid Polypeptide and proIAPP Processing Intermediates journal February 2011
Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers journal January 2012
Kinetic and Conformational Insights into Islet Amyloid Polypeptide Self-Assembly Using a Biarsenical Fluorogenic Probe journal January 2018
Mechanisms of islet amyloidosis toxicity in type 2 diabetes journal January 2013
Fluorescence microscopy with thioflavine-T in the diagnosis of amyloid journal October 1963
Characterizing the assembly behaviors of human amylin: a perspective derived from C-terminal variants journal January 2013
Peptide Conformation and Supramolecular Organization in Amylin Fibrils:  Constraints from Solid-State NMR † journal November 2007
Efficient Microwave-Assisted Synthesis of Human Islet Amyloid Polypeptide Designed to Facilitate the Specific Incorporation of Labeled Amino Acids journal November 2010
Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts journal February 2010
ANS Binding Reveals Common Features of Cytotoxic Amyloid Species journal June 2010
Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid journal December 2007
Identification of Hot Regions of the Aβ-IAPP Interaction Interface as High-Affinity Binding Sites in both Cross- and Self-Association journal March 2010
Protein Misfolding, Functional Amyloid, and Human Disease journal June 2006
Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases journal April 2002
Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic β-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity journal March 2019
Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. journal December 1987
Molecular links between Alzheimer’s disease and diabetes mellitus journal October 2013
Different Fates of Alzheimer’s Disease Amyloid-β Fibrils Remodeled by Biocompatible Small Molecules journal December 2012

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