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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
Author(s) -
Klingstedt Therése,
Shirani Hamid,
Åslund K. O. Andreas,
Cairns Nigel J.,
Sigurdson Christina J.,
Goedert Michel,
Nilsson K. Peter R.
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201301463
Subject(s) - thiophene , thioflavin , chemistry , fluorescence , congo red , conjugated system , amyloid (mycology) , benzothiazole , biophysics , polymer , biochemistry , organic chemistry , biology , disease , alzheimer's disease , medicine , inorganic chemistry , physics , pathology , quantum mechanics , adsorption
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 and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic 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: 1) replacing thiophene units with selenophene or phenylene moieties, or 2) 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 disease‐associated protein aggregates.