Modulating Protein-Protein Interactions with Visible-Light-Responsive Peptide Backbone Photoswitches

Area of Science:

• Biochemistry
• Chemical Biology
• Molecular Biology

Background:

• Protein-protein interactions (PPI) are crucial for cellular functions and disease development.
• Modulating PPI is a promising therapeutic strategy.
• Optical control over PPI offers precise spatiotemporal regulation.

Purpose of the Study:

• To synthesize and characterize novel photoswitchable peptidomimetics for optical control of PPI.
• To investigate the light-responsive properties and binding affinity of these molecules.
• To explore their potential in inhibiting enzymatic activity via PPI disruption.

Main Methods:

• Synthesis and characterization of azobenzene-based photoswitches.
• Visible-light-induced reversible isomerization studies.
• Nanomolar binding affinity assays.
• Enzymatic activity inhibition assays.
• Crystal structure determination, molecular docking, and dynamics simulations.

Main Results:

• Two novel visible-light-responsive peptide backbone photoswitches were synthesized.
• The peptidomimetics exhibited fast, reversible isomerization with low photochemical fatigue under blue/green light.
• Both compounds showed nanomolar binding affinity to the target protein.
• The lead compound demonstrated isomer-dependent differences in protein binding and PPI disruption, leading to inhibition of enzymatic activity.

Conclusions:

• Developed photoswitchable peptidomimetics enable optical control over protein-protein interactions.
• These molecules represent a new class of tools for modulating biological processes.
• Structural and computational analyses provide insights for designing future photoswitchable PPI modulators.