Ligands for Protein Fibrils of Amyloid-β, α‑Synuclein, and Tau

Amyloid fibrils are characteristic features of many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The use of small molecule ligands that bind to amyloid fibrils underpins both fundamental research aiming to better understand the pathology of neurodegenerative disease, and clinical research aiming to develop diagnostic tools for these diseases. To date, a large number of amyloid-binding ligands have been reported in the literature, predominantly targeting protein fibrils composed of amyloid-β (Aβ), tau, and α-synuclein (αSyn) fibrils. Fibrils formed by a particular protein can adopt a range of possible morphologies, but protein fibrils formed in vivo possess disease-specific morphologies, highlighting the need for morphology-specific amyloid-binding ligands. This review details the morphologies of Aβ, tau, and αSyn fibril polymorphs that have been reported as a result of structural work and describes a database of amyloid-binding ligands containing 4,288 binding measurements for 2,404 unique compounds targeting Aβ, tau, or αSyn fibrils.