Xanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates

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dc.citation.firstpage12540en_US
dc.citation.journalTitleChemical Scienceen_US
dc.citation.lastpage12549en_US
dc.citation.volumeNumber13en_US
dc.contributor.authorWang, Lushunen_US
dc.contributor.authorHsiung, Chia-Hengen_US
dc.contributor.authorLiu, Xiaojingen_US
dc.contributor.authorWang, Shichaoen_US
dc.contributor.authorLoredo, Axelen_US
dc.contributor.authorZhang, Xinen_US
dc.contributor.authorXiao, Hanen_US
dc.date.accessioned2022-12-13T19:11:17Zen_US
dc.date.available2022-12-13T19:11:17Zen_US
dc.date.issued2022en_US
dc.description.abstractProper three-dimensional structures are essential for maintaining the functionality of proteins and for avoiding pathological consequences of improper folding. Misfolding and aggregation of proteins have been both associated with neurodegenerative disease. Therefore, a variety of fluorogenic tools that respond to both polarity and viscosity have been developed to detect protein aggregation. However, the rational design of highly sensitive fluorophores that respond solely to polarity has remained elusive. In this work, we demonstrate that electron-withdrawing heteroatoms with (d–p)–π* conjugation can stabilize lowest unoccupied molecular orbital (LUMO) energy levels and promote bathochromic shifts. Guided by computational analyses, we have devised a novel series of xanthone-based solvatochromic fluorophores that have rarely been systematically studied. The resulting probes exhibit superior sensitivity to polarity but are insensitive to viscosity. As proof of concept, we have synthesized protein targeting probes for live-cell confocal imaging intended to quantify the polarity of misfolded and aggregated proteins. Interestingly, our results reveal several layers of protein aggregates in a way that we had not anticipated. First, microenvironments with reduced polarity were validated in the misfolding and aggregation of folded globular proteins. Second, granular aggregates of AgHalo displayed a less polar environment than aggregates formed by folded globular protein represented by Htt–polyQ. Third, our studies reveal that granular protein aggregates formed in response to different types of stressors exhibit significant polarity differences. These results show that the solvatochromic fluorophores solely responsive to polarity represent a new class of indicators that can be widely used for detecting protein aggregation in live cells, thus paving the way for elucidating cellular mechanisms of protein aggregation as well as therapeutic approaches to managing intracellular aggregates.en_US
dc.identifier.citationWang, Lushun, Hsiung, Chia-Heng, Liu, Xiaojing, et al.. "Xanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregates." <i>Chemical Science,</i> 13, (2022) Royal Society of Chemistry: 12540-12549. https://doi.org/10.1039/D2SC05004H.en_US
dc.identifier.digitald2sc05004hen_US
dc.identifier.doihttps://doi.org/10.1039/D2SC05004Hen_US
dc.identifier.urihttps://hdl.handle.net/1911/114095en_US
dc.language.isoengen_US
dc.publisherRoyal Society of Chemistryen_US
dc.rightsThis Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licenceen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/en_US
dc.titleXanthone-based solvatochromic fluorophores for quantifying micropolarity of protein aggregatesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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