Cancer Specific CAIX-Targeting Supramolecular Lysosome-Targeting Chimeras (Supra-LYTAC) for Targeted Protein...

Area of Science:

• Biochemistry
• Nanotechnology
• Oncology

Background:

• Targeted protein degradation (TPD) offers a novel therapeutic strategy for diseases.
• Current TPD methods primarily focus on intracellular targets, leaving extracellular and membrane proteins largely undruggable.
• Developing new modalities to target these extracellular proteins is crucial for expanding TPD applications.

Purpose of the Study:

• To develop a novel supramolecular approach for targeted degradation of extracellular cancer proteins.
• To engineer lysosome-targeting chimeras (LYTACs) capable of targeting cancer-specific membrane proteins.
• To demonstrate the efficacy of a supramolecular strategy for enhancing TPD scope.

Main Methods:

• Synthesis of two self-assembling amphiphilic peptides: one for protein of interest (POI) interaction, another for lysosomal endocytosis via a cancer-specific enzyme.
• Co-assembly of peptides into supramolecular nanofibers.
• Development of cancer-specific carbonic anhydrase IX (CAIX)-targeting Supra-LYTACs.
• Demonstration of ternary complex formation and lysosomal internalization for POI degradation.

Main Results:

• Successful co-assembly of peptides into nanofibers capable of spatiotemporal cancer cell targeting.
• Formation of a ternary complex (supramolecular chimeric nanostructure) facilitating targeted delivery.
• Internalization into lysosomes and subsequent degradation of the targeted protein of interest (POI) via lysosomal activity.
• Demonstrated potential for targeting extracellular proteins, specifically CAIX on cancer cells.

Conclusions:

• Supramolecular approaches can effectively expand the capabilities of LYTAC technology.
• The developed Supra-LYTACs offer a promising strategy for targeting and degrading extracellular proteins.
• This work opens new avenues for designing innovative TPD strategies against challenging cancer targets.