Immunoproteasome as a Target for Prodrugs

Area of Science:

• Cellular Biology
• Biochemistry
• Drug Discovery

Background:

• The immunoproteasome (iCP) is an enzyme isoform upregulated during inflammation, differing from the standard proteasome (CP).
• iCP processes peptides crucial for MHC-I presentation, influencing T-cell activation.
• Previous work introduced TBZ-1, a fluorescent probe for monitoring iCP activity.

Purpose of the Study:

• To establish the immunoproteasome (iCP) as a viable enzyme for targeted prodrug activation.
• To demonstrate the release of cytotoxic and protein-degrading payloads mediated by iCP activity.

Main Methods:

• Utilized the iCP recognition sequence from the TBZ-1 probe to design prodrugs.
• Incorporated doxorubicin (cytotoxic drug) and a BRD4 degrader as prodrug payloads.
• Assessed cell death and BRD4 degradation in relation to iCP activity.

Main Results:

• Prodrugs designed with the iCP recognition sequence were activated specifically in iCP-expressing cells.
• iCP-mediated release of doxorubicin induced significant cell death.
• iCP activity was essential for the degradation of the transcription factor BRD4.

Conclusions:

• The immunoproteasome (iCP) is a functional enzyme for targeted prodrug activation.
• iCP-mediated release can deliver diverse therapeutic payloads, including cytotoxic agents and degraders.
• This highlights iCP as a promising target for developing novel cancer therapeutics.