A Universal and Modular Scaffold for Heparanase Activatable Probes and Drugs.

Area of Science:

• Biochemistry
• Enzymology
• Molecular Biology

Background:

• Heparanase (HPSE) is crucial for extracellular matrix remodeling in healing, cancer, inflammation, and viral infections.
• HPSE's therapeutic potential is hindered by a lack of effective research tools.
• Developing novel probes is essential for studying HPSE activity and its role in disease.

Purpose of the Study:

• To design and validate a versatile substrate scaffold for probing HPSE enzymatic activity.
• To create a platform for developing HPSE-responsive imaging agents and drug delivery systems.
• To investigate the influence of electronic properties on HPSE probe reactivity.

Main Methods:

• Design of a disaccharide substrate scaffold with a cleavable linker.
• Synthesis of a fluorogenic, coumarin-based imaging probe utilizing the scaffold.
• Molecular docking and modeling to elucidate probe-enzyme binding interactions.
• Electronic tuning of the scaffold to optimize probe response.

Main Results:

• A universal HPSE-activatable scaffold was successfully designed and demonstrated.
• The scaffold enables the development of HPSE-responsive imaging probes and potentially drug delivery tools.
• Electronic tuning of the scaffold significantly impacts probe response to HPSE.
• Molecular modeling suggests a productive binding mode between the probe and HPSE.

Conclusions:

• The developed scaffold provides a robust and adaptable platform for HPSE research.
• This innovation facilitates the creation of new diagnostic and therapeutic tools targeting HPSE.
• Understanding the electronic influence on probe reactivity is key for future HPSE tool development.