Binding of Polythiophenes to Amyloids: Structural Mapping of the Pharmacophore

Abstract

Luminescent conjugated polythiophenes bind to amyloid proteins with high affinity. Their fluorescence properties, which are modulated by the detailed conformation in the bound state, are highly sensitive to structural features of the amyloid. Polythiophenes therefore represent diagnostic markers for the detection and differentiation of pathological amyloid aggregates. We clarify the binding site and mode of two different polythiophenes to fibrils of the prion domain of the HET-s protein by solid-state NMR and correlate these findings with their fluorescence properties. We demonstrate how amyloid dyes recognize distinct binding sites with specific topological features. Regularly spaced surface charge patterns and well-accessible grooves on the fibril surface define the pharmacophore of the amyloid, which in turn determines the binding mode and fluorescence wavelength of the polythiophene.

Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease

“…Yet by the second passage, the attack rate was 100% and the incubation period decreased by 60% (142 ± 5 dpi), and by third passage the incubation period was similar to ME7 in WT mice (177 ± 5 dpi), suggestive time distribution was shifted in the Prnp 180Q/196Q mice as compared with the WT mice ( Figure 4). Since theoretical calculations and solid-state NMR experiments have verified that the binding mode and the optical properties of the oligothiophene are determined by regularly spaced surface charge patterns and highly accessible grooves on the fibril surface (48)(49)(50), the observed differences in life time distribution are most likely due to PrP structural variations in Prnp 180Q/196Q mice. ME7 and mCWD prions in Prnp 180Q/196Q mice largely consist of ADAM10-cleaved PrP.…”

Binding sites for luminescent amyloid biomarkers from non-biased molecular dynamics simulations

“…• The interactions between negatively charged probe groups and lysine have been proposed before as main interaction sites for both Congo-red 13 and LCO probes 14,28 in combination with prions. These results were obtained from evidence-based docking, based on more approximate structures than what we employ in the present study.…”

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

“…The molecule encounters an accessible elongated groove as the primary binding site. To optimally bind the amyloid, the anionic LCP/LCO must pair with specific regioregular arrangements of positively charged amino acids on the amyloid surface that match its negative charges [104]. Whilst these are initial studies performed on yeast prions, they can offer available polymorphic test beds for amyloid-targeting probes.…”