Picomolar-sensitive β-amyloid fibril fluorophores by tailoring the hydrophobicity of biannulated π-elongated dioxaborine-dyes
Jusung An, Peter Verwilst, Hira Aziz, Jin Woo Shin, Sungsu Lim, Ilwha Kim, Yun Kyung Kim, Jong Seung Kim
Abstract
The pathological origin of Alzheimer's disease (AD) is still shrouded in mystery, despite intensive worldwide research efforts. The selective visualization of β-amyloid (Aβ), the most abundant proteinaceous deposit in AD, is pivotal to reveal AD pathology. To date, several small-molecule fluorophores for Aβ species have been developed, with increasing binding affinities. In the current work, two organic small-molecule dioxaborine-derived fluorophores were rationally designed through tailoring the hydrophobicity with the aim to enhance the binding affinity for Aβ1-42 fibrils —while concurrently preventing poor aqueous solubility—via biannulate donor motifs in D-π-A dyes. An unprecedented sub-nanomolar affinity was found (Kd = 0.62 ± 0.33 nM) and applied to super-sensitive and red-emissive fluorescent staining of amyloid plaques in cortical brain tissue ex vivo. These fluorophores expand the dioxaborine-curcumin-based family of Aβ-sensitive fluorophores with a promising new imaging agent.