A Photoregulated Peptidase Mimic

Area of Science:

• Biochemistry and Chemical Biology
• Enzyme Mimicry and Catalysis
• Photopharmacology

Background:

• Proteases and peptidases are essential enzymes involved in diverse biological functions.
• Their activity relies on precise substrate binding and peptide bond hydrolysis.
• Controlling enzymatic activity with external stimuli remains a significant challenge.

Purpose of the Study:

• To design and synthesize a novel small-molecule light-activated peptidase (SLAP) mimic.
• To investigate light-induced control over peptidase activity.
• To explore applications in targeted protein degradation.

Main Methods:

• Development of a glucose-linked photoswitch-imidazole triad as an enzyme mimic.
• Utilizing light to modulate the distance between key catalytic residues and the substrate-binding site.
• Assessing catalytic hydrolysis using small molecules, FRET-based substrates, and cellular proteins.

Main Results:

• The SLAP mimic demonstrated light-controllable peptidase activity.
• The cis isomer showed a ~300-fold increase in catalytic activity compared to the trans isomer.
• Successful hydrolysis of various substrates, including complex cellular proteins, was achieved.

Conclusions:

• A functional light-activated peptidase mimic was successfully created.
• Light provides precise spatiotemporal control over enzymatic activity.
• This technology offers novel avenues for applications in targeted protein degradation and chemical biology.