Amino Acid Functionalization Influences the Binding of Thiophene‐Vinylene‐Benzothiazolium‐Based Fluorescent Ligands to Protein Deposits in Tissue Sections With Alzheimer’s Disease Pathology
- 1Department of Physics Chemistry and Biology Linköping University Linköping Sweden
- 2Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis Indiana USA
- 3Department of Physics The Norwegian University of Science and Technology, NTNU Trondheim Norway
Abstract
Detecting and distinguishing between structurally diverse protein aggregates involved in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), remain key challenges in the development of molecular imaging tools. Recently, bi‐thiophene‐vinyl‐benzothiazoliums (bTVBTs), a class of thiophene‐based optical ligands, were synthesized and shown to enable selective labeling of tau pathology in AD brain tissue. Building on this framework, we report here the design and evaluation of a novel series of bTVBT ligands functionalized with L‐amino acids (glycine, alanine, valine, tyrosine, or glutamate) to explore their influence on ligand–filament interactions. When applied to sporadic AD brain tissue sections, the ligands displayed preferential binding to tau deposits when using 100 nM ligand, whereas all ligands bound to both amyloid‐β (Aβ) and tau aggregates at higher concentrations. The glycine‐functionalized bTVBT scaffold demonstrated the strongest fluorescence upon binding and was labeling all types of tau inclusions present in sAD brain tissue, whereas the glutamate‐functionalized ligand was the least potent. Thus, the chemical nature of the amino acid influenced the binding mode of the ligand to protein deposits. The observed trend in the ligands’ binding mode to the protein aggregates could also be correlated with distinct solvatochromic effects, indicating that certain amino acid side chains interfere with favorable interligand π–π stacking, thereby reducing binding specificity. Collectively, these results pinpoint that minor chemical alterations of the bTVBT scaffold influence the binding mode of the ligands to protein deposits, and we foresee that our findings will aid in designing ligands targeting proteinaceous aggregated species in AD and related neurodegenerative diseases.
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BibTeX
@article{bjork2026amino,
title = {{Amino Acid Functionalization Influences the Binding of Thiophene‐Vinylene‐Benzothiazolium‐Based Fluorescent Ligands to Protein Deposits in Tissue Sections With Alzheimer’s Disease Pathology}},
author = {Linnea Björk and Ruben Vidal and Bernardino Ghetti and Mikael Lindgren and Therése Klingstedt and K. Peter R. Nilsson},
journal = {Chemmedchem},
year = {2026},
month = nov,
doi = {10.1002/cmdc.70558},
url = {https://doi.org/10.1002/cmdc.70558},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Amino Acid Functionalization Influences the Binding of Thiophene‐Vinylene‐Benzothiazolium‐Based Fluorescent Ligands to Protein Deposits in Tissue Sections With Alzheimer’s Disease Pathology
AU - Linnea Björk
AU - Ruben Vidal
AU - Bernardino Ghetti
AU - Mikael Lindgren
AU - Therése Klingstedt
AU - K. Peter R. Nilsson
PY - 2026
DA - 2026/11/03
JO - Chemmedchem
DO - 10.1002/cmdc.70558
UR - https://doi.org/10.1002/cmdc.70558
AB - Detecting and distinguishing between structurally diverse protein aggregates involved in various neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), remain key challenges in the development of molecular imaging tools. Recently, bi‐thiophene‐vinyl‐benzothiazoliums (bTVBTs), a class of thiophene‐based optical ligands, were synthesized and shown to enable selective labeling of tau pathology in AD brain tissue. Building on this framework, we report here the design and evaluation of a novel series of bTVBT ligands functionalized with L‐amino acids (glycine, alanine, valine, tyrosine, or glutamate) to explore their influence on ligand–filament interactions. When applied to sporadic AD brain tissue sections, the ligands displayed preferential binding to tau deposits when using 100 nM ligand, whereas all ligands bound to both amyloid‐β (Aβ) and tau aggregates at higher concentrations. The glycine‐functionalized bTVBT scaffold demonstrated the strongest fluorescence upon binding and was labeling all types of tau inclusions present in sAD brain tissue, whereas the glutamate‐functionalized ligand was the least potent. Thus, the chemical nature of the amino acid influenced the binding mode of the ligand to protein deposits. The observed trend in the ligands’ binding mode to the protein aggregates could also be correlated with distinct solvatochromic effects, indicating that certain amino acid side chains interfere with favorable interligand π–π stacking, thereby reducing binding specificity. Collectively, these results pinpoint that minor chemical alterations of the bTVBT scaffold influence the binding mode of the ligands to protein deposits, and we foresee that our findings will aid in designing ligands targeting proteinaceous aggregated species in AD and related neurodegenerative diseases.
SN - 1860-7179
SN - 1860-7187
ER -