Solvation-Guided Design of Fluorescent Probes for Discrimination of Amyloids

Abstract 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...

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Autores principales:	Kevin J. Cao, Kristyna M. Elbel, Jessica L. Cifelli, Jordi Cirera, Christina J. Sigurdson, Francesco Paesani, Emmanuel A. Theodorakis, Jerry Yang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1da911951350412fa1fd1e0d6610d4fc
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spelling	oai:doaj.org-article:1da911951350412fa1fd1e0d6610d4fc2021-12-02T11:41:03ZSolvation-Guided Design of Fluorescent Probes for Discrimination of Amyloids10.1038/s41598-018-25131-22045-2322https://doaj.org/article/1da911951350412fa1fd1e0d6610d4fc2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25131-2https://doaj.org/toc/2045-2322Abstract 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 β-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.Kevin J. CaoKristyna M. ElbelJessica L. CifelliJordi CireraChristina J. SigurdsonFrancesco PaesaniEmmanuel A. TheodorakisJerry YangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kevin J. Cao Kristyna M. Elbel Jessica L. Cifelli Jordi Cirera Christina J. Sigurdson Francesco Paesani Emmanuel A. Theodorakis Jerry Yang Solvation-Guided Design of Fluorescent Probes for Discrimination of Amyloids
description	Abstract 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 β-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.
format	article
author	Kevin J. Cao Kristyna M. Elbel Jessica L. Cifelli Jordi Cirera Christina J. Sigurdson Francesco Paesani Emmanuel A. Theodorakis Jerry Yang
author_facet	Kevin J. Cao Kristyna M. Elbel Jessica L. Cifelli Jordi Cirera Christina J. Sigurdson Francesco Paesani Emmanuel A. Theodorakis Jerry Yang
author_sort	Kevin J. Cao
title	Solvation-Guided Design of Fluorescent Probes for Discrimination of Amyloids
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
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/1da911951350412fa1fd1e0d6610d4fc
work_keys_str_mv	AT kevinjcao solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT kristynamelbel solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT jessicalcifelli solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT jordicirera solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT christinajsigurdson solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT francescopaesani solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT emmanuelatheodorakis solvationguideddesignoffluorescentprobesfordiscriminationofamyloids AT jerryyang solvationguideddesignoffluorescentprobesfordiscriminationofamyloids
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Solvation-Guided Design of Fluorescent Probes for Discrimination of Amyloids

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