Light-driven release of cucurbit[8]uril from a bivalent cage

Area of Science:

• Supramolecular Chemistry
• Chemical Biology
• Enzyme Engineering

Background:

• Temporal control over supramolecular systems is crucial for applications like modulating protein activity.
• Light-triggered systems offer precise control for interfacing with biological systems, particularly enzymes.
• Cucurbit[8]uril (CB[8]) is a macrocyclic host with applications in molecular recognition and assembly.

Purpose of the Study:

• To develop a light-inducible system for releasing cucurbit[8]uril (CB[8]).
• To demonstrate the subsequent activation of a light-insensitive proteolytic enzyme, caspase-9, using the released CB[8].
• To create a novel platform for switchable cucurbituril applications.

Main Methods:

• Design and synthesis of a bivalent cage molecule with high affinity for CB[8].
• Utilizing UV light to induce the release of CB[8] from the cage.
• Investigating the affinity switching of the cage-CB[8] complex in the (sub-)micromolar range.
• Demonstrating the dimerization and activation of caspase-9 by the released CB[8].

Main Results:

• A bivalent cage molecule was engineered to bind CB[8] with significantly higher affinity (100-fold) compared to its UV-inactivated forms.
• Light-induced release of CB[8] was achieved, with affinity switching occurring at biologically relevant (sub-)micromolar concentrations.
• The released CB[8] successfully dimerized and activated caspase-9, an enzyme not directly responsive to light.
• The developed system provides temporal control over enzyme activation through light-induced supramolecular events.

Conclusions:

• The light-responsive caged CB[8] system offers a novel method for temporal control over supramolecular interactions.
• This platform enables the activation of light-insensitive enzymes through external light stimuli.
• The findings present a versatile approach for tuning and applying switchable cucurbiturils in various contexts.
• This work expands the possibilities for light-controlled molecular systems in chemical biology and beyond.