Highly tunable bimane-based fluorescent probes: design, synthesis, and application as a selective amyloid binding dye

Yarra Venkatesh; Nicholas P Marotta; Virginia M-Y Lee; E James Petersson

doi:10.1039/d4sc00024b

Highly tunable bimane-based fluorescent probes: design, synthesis, and application as a selective amyloid binding dye

Chem Sci. 2024 Mar 26;15(16):6053-6063. doi: 10.1039/d4sc00024b. eCollection 2024 Apr 24.

Authors

Yarra Venkatesh¹, Nicholas P Marotta², Virginia M-Y Lee², E James Petersson^{1

3}

Affiliations

¹ Department of Chemistry, University of Pennsylvania 231 South 34th Street Philadelphia PA 19104 USA ejpetersson@sas.upenn.edu.
² Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania 3600 Spruce Street Philadelphia PA 19104 USA.
³ Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania 421 Curie Boulevard Philadelphia PA 19104 USA.

Abstract

Small molecule fluorescent probes are indispensable tools for a broad range of biological applications. Despite many probes being available, there is still a need for probes where photophysical properties and biological selectivity can be tuned as desired. Here, we report the rational design and synthesis of a palette of fluorescent probes based on the underexplored bimane scaffold. The newly developed probes with varied electronic properties show tunable absorption and emission in the visible region with large Stokes shifts. Probes featuring electron-donating groups exhibit rotor effects that are sensitive to polarity and viscosity by "intramolecular charge transfer" (ICT) and twisted intramolecular charge transfer (TICT) mechanisms, respectively. These properties enable their application as "turn-on" fluorescent probes to detect fibrillar aggregates of the α-synuclein (αS) protein that are a hallmark of Parkinson's disease (PD). One probe shows selective binding to αS fibrils relative to soluble proteins in cell lysates and amyloid fibrils of tau and amyloid-β. Finally, we demonstrate the diagnostic potential of the probe in selectively detecting αS fibrils amplified from PD with dementia (PDD) patient samples.