Solvation-guided design of fluorescent probes for discrimination of amyloids

The deposition of insoluble protein aggregates in the brain is a hallmark of many neurodegenerative diseases. While their exact role in neurodegeneration remains unclear, the presence of these amyloid deposits often precedes clinical symptoms. As a result, recent progress in imaging methods that uti...

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Autores: Cao, Kevin J., Elbel, Kristyna M., Cifelli, Jessica L., Cirera Fernández, Jordi, Sigurdson, Christina J., Paesani, Francesco, Theodorakis, Emmanuel A., Yang, Jerry
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/126311
Acesso em linha:https://hdl.handle.net/2445/126311
Access Level:acceso abierto
Palavra-chave:Malalties neurodegeneratives
Proteïnes
Amiloïdosi
Neurodegenerative Diseases
Proteins
Amyloidosis
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spelling Solvation-guided design of fluorescent probes for discrimination of amyloidsCao, Kevin J.Elbel, Kristyna M.Cifelli, Jessica L.Cirera Fernández, JordiSigurdson, Christina J.Paesani, FrancescoTheodorakis, Emmanuel A.Yang, JerryMalalties neurodegenerativesProteïnesAmiloïdosiNeurodegenerative DiseasesProteinsAmyloidosisThe deposition of insoluble protein aggregates in the brain is a hallmark of many neurodegenerative diseases. While their exact role in neurodegeneration remains unclear, the presence of these amyloid deposits often precedes clinical symptoms. As a result, recent progress in imaging methods that utilize amyloid-specific small molecule probes have become a promising avenue for antemortem disease diagnosis. Here, we present a series of amino-aryl cyanoacrylate (AACA) fluorophores that show a turn-on fluorescence signal upon binding to amyloids in solution and in tissue. Using a theoretical model for environmental sensitivity of fluorescence together with ab initio computational modeling of the effects of polar environment on electron density distribution and conformational dynamics, we designed, synthesized, and evaluated a set of fluorophores that (1) bind to aggregated forms of Alzheimer's-related beta-amyloid peptides with low micromolar to high nanomolar affinities and (2) have the capability to fluorescently discriminate different amyloids based on differences in amino acid composition within the binding pocket through exploitation of their solvatochromic properties. These studies showcase the rational design of a family of amyloid-binding imaging agents that could be integrated with new optical approaches for the clinical diagnosis of amyloidoses, where accurate identification of the specific neurodegenerative disease could aid in the selection of a proper course for treatment.Nature Publishing Group2018201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion13 p.application/pdfhttps://hdl.handle.net/2445/126311Articles publicats en revistes (Química Inorgànica i Orgànica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1038/s41598-018-25131-2Scientific Reports, 2018, vol. 8, p. 6950https://doi.org/10.1038/s41598-018-25131-2cc-by (c) Cao et al., 2018http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1263112026-05-29T05:05:01Z
dc.title.none.fl_str_mv Solvation-guided design of fluorescent probes for discrimination of amyloids
title Solvation-guided design of fluorescent probes for discrimination of amyloids
spellingShingle Solvation-guided design of fluorescent probes for discrimination of amyloids
Cao, Kevin J.
Malalties neurodegeneratives
Proteïnes
Amiloïdosi
Neurodegenerative Diseases
Proteins
Amyloidosis
title_short Solvation-guided design of fluorescent probes for discrimination of amyloids
title_full Solvation-guided design of fluorescent probes for discrimination of amyloids
title_fullStr Solvation-guided design of fluorescent probes for discrimination of amyloids
title_full_unstemmed Solvation-guided design of fluorescent probes for discrimination of amyloids
title_sort Solvation-guided design of fluorescent probes for discrimination of amyloids
dc.creator.none.fl_str_mv Cao, Kevin J.
Elbel, Kristyna M.
Cifelli, Jessica L.
Cirera Fernández, Jordi
Sigurdson, Christina J.
Paesani, Francesco
Theodorakis, Emmanuel A.
Yang, Jerry
author Cao, Kevin J.
author_facet Cao, Kevin J.
Elbel, Kristyna M.
Cifelli, Jessica L.
Cirera Fernández, Jordi
Sigurdson, Christina J.
Paesani, Francesco
Theodorakis, Emmanuel A.
Yang, Jerry
author_role author
author2 Elbel, Kristyna M.
Cifelli, Jessica L.
Cirera Fernández, Jordi
Sigurdson, Christina J.
Paesani, Francesco
Theodorakis, Emmanuel A.
Yang, Jerry
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties neurodegeneratives
Proteïnes
Amiloïdosi
Neurodegenerative Diseases
Proteins
Amyloidosis
topic Malalties neurodegeneratives
Proteïnes
Amiloïdosi
Neurodegenerative Diseases
Proteins
Amyloidosis
description The deposition of insoluble protein aggregates in the brain is a hallmark of many neurodegenerative diseases. While their exact role in neurodegeneration remains unclear, the presence of these amyloid deposits often precedes clinical symptoms. As a result, recent progress in imaging methods that utilize amyloid-specific small molecule probes have become a promising avenue for antemortem disease diagnosis. Here, we present a series of amino-aryl cyanoacrylate (AACA) fluorophores that show a turn-on fluorescence signal upon binding to amyloids in solution and in tissue. Using a theoretical model for environmental sensitivity of fluorescence together with ab initio computational modeling of the effects of polar environment on electron density distribution and conformational dynamics, we designed, synthesized, and evaluated a set of fluorophores that (1) bind to aggregated forms of Alzheimer's-related beta-amyloid peptides with low micromolar to high nanomolar affinities and (2) have the capability to fluorescently discriminate different amyloids based on differences in amino acid composition within the binding pocket through exploitation of their solvatochromic properties. These studies showcase the rational design of a family of amyloid-binding imaging agents that could be integrated with new optical approaches for the clinical diagnosis of amyloidoses, where accurate identification of the specific neurodegenerative disease could aid in the selection of a proper course for treatment.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/126311
url https://hdl.handle.net/2445/126311
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41598-018-25131-2
Scientific Reports, 2018, vol. 8, p. 6950
https://doi.org/10.1038/s41598-018-25131-2
dc.rights.none.fl_str_mv cc-by (c) Cao et al., 2018
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Cao et al., 2018
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Química Inorgànica i Orgànica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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