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The structural basis for optimal performance of oligothiophene based fluorescent amyloid ligands: Conformational flexibility is essential for spectral assignment of a diversity of protein aggregates
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Department of Neurology, Alzheimer’s Disease Research Center, Washington University St. Louis, United States.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Protein misfolding diseases are characterized by deposition of protein aggregates and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as Thioflavin T (ThT) and Congo red. Herein, the molecular requirements for achieving LCOs able to detect non-thioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by i) replacing thiophene units with selenophene or phenylene moieties or ii) alternating the anionic substituents along the  thiophene backbone. In addition, two asymmetric tetrameric ligands were  generated. Overall, the results from this study identified conformational  freedom and extended conjugation of the conjugated backbone as crucial  determinants for obtaining superior thiophene-based optical ligands for  sensitive detection and spectral assignment of diseaseassociated protein aggregates.

Keyword [en]
Luminescent conjugated oligothiophenes, protein aggregates, fluorescence, Alzheimer´s disease, prion
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-92771OAI: oai:DiVA.org:liu-92771DiVA: diva2:622387
Available from: 2013-05-21 Created: 2013-05-21 Last updated: 2014-04-08
In thesis
1. Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates
Open this publication in new window or tab >>Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the unique optical properties of fluorescent ligands termed luminescent conjugated oligothiophenes (LCOs) have been used to study a variety of protein aggregates associated with human protein misfolding disease. This heterogeneous group of diseases contains well known and fatal members such as Alzheimer´s and Huntington´s disease and the development of sensitive tools for the detection and characterization of protein aggregates is crucial for unravelling the complexity of these pathologies. Conventionally, the molecular dyes Congo red and thioflavin T (ThT) have been the primary choices for detecting and monitoring protein misfolding events. However, the rigid scaffold of both Congo red and ThT only offers an on or off mode and limits their ability to make fine distinctions at the molecular level. In contrast, LCOs have a flexible conjugated backbone and in addition to detect a broader subset of misfolded proteins, LCO can be used to visualize the heterogeneity of protein aggregates.

The work presented in this thesis has given novel insights regarding the close connection between LCO design and optical performance. By altering the backbone length and the arrangement of substituents as well as replacing thiophene units with moieties affecting conjugation length and conformational freedom, the structural requirements of an optimal LCO for a certain application have been revealed. LCOs having a pentameric thiophene backbone with carboxyl end-groups were able to i) cross the blood-brain barrier and selectively stain cerebral amyloid β (Aβ) plaques, ii) detect non-thioflavinophilic Aβ aggregates and non-congophilic prion aggregates, iii) spectrally discriminate Aβ from tau aggregates and iiii) strongly label protein inclusion bodies. However, in some applications this design was outdone by others and in general, the conjugation length and the level of conformational freedom of the backbone were important determinants of the performance of the LCO.

Overall, the findings in this thesis illustrate how small alterations in the LCO molecular scaffold may have large impact on the ligand properties. The results highlight the importance of having a toolbox of diverse ligands in order to increase our knowledge regarding the complex nature of protein aggregates.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 81 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1518
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-92772 (URN)978-91-7519-623-7 (ISBN)
Public defence
2013-05-31, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (Swedish)
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Supervisors
Available from: 2013-05-21 Created: 2013-05-21 Last updated: 2014-04-08Bibliographically approved

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Klingstedt, TheréseShirani, HamidÅslund, K. O. AndreasNilsson, K. Peter R.

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