Highly tunable bimane-based fluorescent probes: design, synthesis, and application as a selective amyloid binding dye
Yarra Venkatesh1, Nicholas P Marotta2, Virginia M-Y Lee2
1Department of Chemistry, University of Pennsylvania 231 South 34th Street Philadelphia PA 19104 USA ejpetersson@sas.upenn.edu.
Chemical Science
|April 26, 2024
Summary
Researchers developed new fluorescent probes using the bimane scaffold for detecting alpha-synuclein (αS) protein aggregates. These probes show potential for diagnosing Parkinson's disease (PD) by selectively identifying αS fibrils in patient samples.
Area of Science:
- Chemical Biology
- Biochemistry
- Neuroscience
Background:
- Small molecule fluorescent probes are crucial for biological research.
- There is a need for probes with tunable photophysical properties and biological selectivity.
- The bimane scaffold remains underexplored for probe development.
Purpose of the Study:
- To rationally design and synthesize a novel palette of fluorescent probes based on the bimane scaffold.
- To investigate the photophysical properties and biological selectivity of these new probes.
- To explore their application in detecting alpha-synuclein (αS) fibrils associated with Parkinson's disease (PD).
Main Methods:
- Rational design and synthesis of bimane-based fluorescent probes with varied electronic properties.
- Characterization of photophysical properties including absorption, emission, and Stokes shifts.
- Evaluation of probe sensitivity to polarity and viscosity via intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) mechanisms.
- Assessment of selective binding to αS fibrils in cell lysates and comparison with other amyloid fibrils.
- Demonstration of diagnostic potential using patient-derived samples.
Main Results:
- A palette of fluorescent probes based on the bimane scaffold was successfully synthesized.
- Probes exhibited tunable absorption and emission in the visible region with large Stokes shifts.
- Electron-donating groups induced rotor effects sensitive to polarity and viscosity.
- "Turn-on" fluorescent probes were developed capable of detecting αS fibrils.
- One probe demonstrated selective binding to αS fibrils over soluble proteins and other amyloid fibrils (tau, amyloid-β).
- The probe successfully detected αS fibrils amplified from Parkinson's disease with dementia (PDD) patient samples.
Conclusions:
- The developed bimane-based fluorescent probes offer tunable photophysical properties and enhanced biological selectivity.
- These probes serve as effective "turn-on" sensors for detecting αS fibrillar aggregates.
- The findings highlight the diagnostic potential of these probes for Parkinson's disease and related dementias.
