scholarly journals Catechol-Containing Compounds are a Broad Class of Amyloid Inhibitors: Redox State is a Key Determinant of the Inhibitory Activities

2020 ◽  
Author(s):  
Paul Velander ◽  
Ling Wu ◽  
Sherry B. Hildreth ◽  
Nancy J. Vogelaar ◽  
Biswarup Mukhopadhyay ◽  
...  

ABSTRACTMechanisms of amyloid inhibition remains poorly understood, in part because most protein targets of amyloid assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based mechanistic elucidation. Herein we employed a small molecule screening approach to identify inhibitors against three prototype amyloidogenic proteins: amylin, Aβ and tau. One remarkable class of inhibitors identified was catechol-containing compounds and redox-related quinones/anthraquinones. Further mechanistic studies determined that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities.

2020 ◽  
Author(s):  
Paul Velander ◽  
Ling Wu ◽  
Sherry B. Hildreth ◽  
Nancy J. Vogelaar ◽  
Biswarup Mukhopadhyay ◽  
...  

Abstract Background: A range of neurodegenerative and related aging diseases, such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based mechanistic elucidation. Methods: Herein we employed a small molecule screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Ab and tau. We further systematically investigated selected class of inhibitors under aerobic and anaerobic conditions to uncover a key determinant of the inhibitory activities.Results: One remarkable class of inhibitors identified from all three parallel screenings against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Further mechanistic studies determined that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. Conclusion: Our small molecule library screening platform was able to identify a broad class of amyloid inhibitors. Redox was found to be a key factor not only regulating the inhibitory activities but also involving the mechanism of inhibition. The molecular insights we gained not only explain why a large number of catechol-containing natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases.


1990 ◽  
Vol 265 (8) ◽  
pp. 4583-4591 ◽  
Author(s):  
J D Pearson ◽  
D B DeWald ◽  
W R Mathews ◽  
N M Mozier ◽  
H A Zürcher-Neely ◽  
...  

2016 ◽  
Vol 22 (10) ◽  
Author(s):  
Carlyle Ribeiro Lima ◽  
Nicolas Carels ◽  
Ana Carolina Ramos Guimaraes ◽  
Pierre Tufféry ◽  
Philippe Derreumaux

2021 ◽  
Author(s):  
Carlos Rodriguez-Pardo ◽  
Gaurav Sharma

<div>For multiprimary displays that have four or more primaries, a color may be reproduced using multiple alternative control vectors. We provide a complete characterization of the Metameric Control Set (MCS), i.e., the set of control vectors that reproduce a given color on the display. Specifically, we show that MCS is a convex polytope whose vertices are control vectors obtained from (parallelepiped) tilings of the gamut, i.e., the range of colors that the display can produce. The mathematical framework that we develop: (a) characterizes gamut tilings in terms of fundamental building blocks called facet spans, (b) establishes that the vertices of the MCS are fully characterized by the tilings of the gamut, and (c) introduces a methodology for the efficient enumeration of gamut tilings. The framework reveals the fundamental inter-relations between the geometry of the MCS and the geometry of the gamut developed in a companion Part I paper, and provides insight into alternative strategies for color control. Our characterization of tilings and the strategy for their enumeration also advance knowledge in geometry, providing new approaches and computational results for the enumeration of tilings for a broad class of zonotopes in R<sup>3</sup>.</div>


Author(s):  
Yongmei Feng ◽  
Gaurav Pathria ◽  
Susanne Heynen-Genel ◽  
Michael Jackson ◽  
Brian James ◽  
...  

Chemosphere ◽  
2018 ◽  
Vol 194 ◽  
pp. 602-613 ◽  
Author(s):  
Susan A. Cumberland ◽  
Barbara Etschmann ◽  
Joël Brugger ◽  
Grant Douglas ◽  
Katy Evans ◽  
...  
Keyword(s):  

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Arne Raasakka ◽  
Petri Kursula

Abstract Objective Oligodendrocytes account for myelination in the central nervous system. During myelin compaction, key proteins are translated in the vicinity of the myelin membrane, requiring targeted mRNA transport. Quaking isoform 6 (QKI6) is a STAR domain-containing RNA transport protein, which binds a conserved motif in the 3′-UTR of certain mRNAs, affecting the translation of myelination-involved proteins. RNA binding has been earlier structurally characterized, but information about full-length QKI6 conformation is lacking. Based on known domains and structure predicitons, we expected full-length QKI6 to be flexible and carry disordered regions. Hence, we carried out biophysical and structural characterization of human QKI6. Results We expressed and purified full-length QKI6 and characterized it using mass spectrometry, light scattering, small-angle X-ray scattering, and circular dichroism spectroscopy. QKI6 was monodisperse, folded, and mostly dimeric, being oxidation-sensitive. The C-terminal tail was intrinsically disordered, as predicted. In the absence of RNA, the RNA-binding subdomain is likely to present major flexibility. In thermal stability assays, a double sequential unfolding behaviour was observed in the presence of phosphate, which may interact with the RNA-binding domain. The results confirm the flexibility and partial disorder of QKI6, which may be functionally relevant.


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