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Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure

Several neurodegenerative diseases are driven by misfolded proteins that assemble into soluble aggregates. These “toxic oligomers” have been associated with a plethora of cellular dysfunction and dysregulation, however the structural features underlying their toxicity are poorly understood. A major...

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Autores principales: Hilt, Silvia, Liu, Ruiwu, Maezawa, Izumi, Rojalin, Tatu, Aung, Hnin H., Budamagunta, Madhu, Slez, Ryan, Gong, Qizhi, Carney, Randy P., Voss, John C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204515/
https://www.ncbi.nlm.nih.gov/pubmed/35720993
http://dx.doi.org/10.3389/fchem.2022.896386
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author Hilt, Silvia
Liu, Ruiwu
Maezawa, Izumi
Rojalin, Tatu
Aung, Hnin H.
Budamagunta, Madhu
Slez, Ryan
Gong, Qizhi
Carney, Randy P.
Voss, John C.
author_facet Hilt, Silvia
Liu, Ruiwu
Maezawa, Izumi
Rojalin, Tatu
Aung, Hnin H.
Budamagunta, Madhu
Slez, Ryan
Gong, Qizhi
Carney, Randy P.
Voss, John C.
author_sort Hilt, Silvia
collection PubMed
description Several neurodegenerative diseases are driven by misfolded proteins that assemble into soluble aggregates. These “toxic oligomers” have been associated with a plethora of cellular dysfunction and dysregulation, however the structural features underlying their toxicity are poorly understood. A major impediment to answering this question relates to the heterogeneous nature of the oligomers, both in terms of structural disorder and oligomer size. This not only complicates elucidating the molecular etiology of these disorders, but also the druggability of these targets as well. We have synthesized a class of bifunctional stilbenes to modulate both the conformational toxicity within amyloid beta oligomers (AβO) and the oxidative stress elicited by AβO. Using a neuronal culture model, we demonstrate this bifunctional approach has the potential to counter the molecular pathogenesis of Alzheimer’s disease in a powerful, synergistic manner. Examination of AβO structure by various biophysical tools shows that each stilbene candidate uniquely alters AβO conformation and toxicity, providing insight towards the future development of structural correctors for AβO. Correlations of AβO structural modulation and bioactivity displayed by each provides insights for future testing in vivo. The multi-target activity of these hybrid molecules represents a highly advantageous feature for disease modification in Alzheimer’s, which displays a complex, multifactorial etiology. Importantly, these novel small molecules intervene with intraneuronal AβO, a necessary feature to counter the cycle of dysregulation, oxidative stress and inflammation triggered during the earliest stages of disease progression.
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spelling pubmed-92045152022-06-18 Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure Hilt, Silvia Liu, Ruiwu Maezawa, Izumi Rojalin, Tatu Aung, Hnin H. Budamagunta, Madhu Slez, Ryan Gong, Qizhi Carney, Randy P. Voss, John C. Front Chem Chemistry Several neurodegenerative diseases are driven by misfolded proteins that assemble into soluble aggregates. These “toxic oligomers” have been associated with a plethora of cellular dysfunction and dysregulation, however the structural features underlying their toxicity are poorly understood. A major impediment to answering this question relates to the heterogeneous nature of the oligomers, both in terms of structural disorder and oligomer size. This not only complicates elucidating the molecular etiology of these disorders, but also the druggability of these targets as well. We have synthesized a class of bifunctional stilbenes to modulate both the conformational toxicity within amyloid beta oligomers (AβO) and the oxidative stress elicited by AβO. Using a neuronal culture model, we demonstrate this bifunctional approach has the potential to counter the molecular pathogenesis of Alzheimer’s disease in a powerful, synergistic manner. Examination of AβO structure by various biophysical tools shows that each stilbene candidate uniquely alters AβO conformation and toxicity, providing insight towards the future development of structural correctors for AβO. Correlations of AβO structural modulation and bioactivity displayed by each provides insights for future testing in vivo. The multi-target activity of these hybrid molecules represents a highly advantageous feature for disease modification in Alzheimer’s, which displays a complex, multifactorial etiology. Importantly, these novel small molecules intervene with intraneuronal AβO, a necessary feature to counter the cycle of dysregulation, oxidative stress and inflammation triggered during the earliest stages of disease progression. Frontiers Media S.A. 2022-05-26 /pmc/articles/PMC9204515/ /pubmed/35720993 http://dx.doi.org/10.3389/fchem.2022.896386 Text en Copyright © 2022 Hilt, Liu, Maezawa, Rojalin, Aung, Budamagunta, Slez, Gong, Carney and Voss. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Hilt, Silvia
Liu, Ruiwu
Maezawa, Izumi
Rojalin, Tatu
Aung, Hnin H.
Budamagunta, Madhu
Slez, Ryan
Gong, Qizhi
Carney, Randy P.
Voss, John C.
Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure
title Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure
title_full Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure
title_fullStr Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure
title_full_unstemmed Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure
title_short Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure
title_sort novel stilbene-nitroxyl hybrid compounds display discrete modulation of amyloid beta toxicity and structure
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204515/
https://www.ncbi.nlm.nih.gov/pubmed/35720993
http://dx.doi.org/10.3389/fchem.2022.896386
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