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

• 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.

Nyckelord

Luminescent conjugated oligothiophenes

protein aggregates

fluorescence

Alzheimer´s disease

prion

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)