Selective Near-Infrared Fluorescent Chemosensors for Human Carboxylesterase 1 Activity

Area of Science:

• Biochemistry
• Chemical Biology
• Pharmacology

Background:

• Carboxylesterase 1 (CES1) is vital for metabolizing ester- and amide-containing drugs, impacting drug efficacy and safety.
• Accurate monitoring of CES1 activity is crucial for clinical guidance in drug therapy.
• Near-infrared (NIR) probes offer advantages for sensitive, noninvasive biological imaging.

Purpose of the Study:

• To develop selective NIR probes for monitoring CES1 activity.
• To characterize the photophysical and enzymatic properties of the lead probe, 1-Me.
• To demonstrate the utility of 1-Me for live-cell imaging of endogenous CES1 activity.

Main Methods:

• Design and synthesis of NIR probes, with a focus on Cy7 derivatives.
• In vitro enzymatic assays to assess probe selectivity and response to CES1.
• Cytotoxicity assays in mammalian cells.
• Live-cell imaging experiments to visualize endogenous CES1 activity.

Main Results:

• The lead probe, 1-Me, demonstrated excellent photophysical properties under physiological conditions.
• 1-Me showed rapid and highly selective fluorogenic response to CES1 over CES2, with significant signal enhancement (64×) and a low limit of detection (0.085 μg/mL).
• 1-Me exhibited minimal cytotoxicity and successfully imaged endogenous CES1 activity in human cell lines.

Conclusions:

• 1-Me is a potent and selective NIR probe for CES1 activity monitoring.
• This probe enables isoform-specific imaging, facilitating drug discovery and precision pharmacotherapy.
• 1-Me holds promise for advancing our understanding of CES1's biological roles and guiding clinical drug utilization.