Circular Bivalent Aptamer Chimeras Leveraging LDLR-Mediated Lysosomal Shuttling for Targeted Protein Degradation

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Membrane protein dysregulation is linked to human diseases, particularly cancer progression.
• Current targeted protein degradation strategies face limitations such as scarce ligands and complex preparation.

Purpose of the Study:

• To introduce a novel lysosome-targeting degradation platform based on circular bivalent aptamer chimeras (CBACs).
• To demonstrate the efficacy of CBACs in degrading specific membrane proteins involved in cancer.

Main Methods:

• CBACs were designed to simultaneously bind the lysosomal shuttle receptor (LDLR) and target membrane proteins.
• The platform leverages the natural LDLR recycling pathway for receptor-mediated endocytosis and lysosomal degradation.
• Degradation of c-Met and PTK7 membrane proteins was assessed in various cancer cell lines.

Main Results:

• CBACs efficiently and selectively degraded c-Met and PTK7 membrane proteins in cancer cells.
• This degradation led to significant apoptosis induction.
• Reduced cancer cell invasion and migration were observed.

Conclusions:

• The CBAC platform offers a modular and effective approach for targeted membrane protein degradation.
• This technology utilizes endogenous trafficking machinery, minimizing potential immunogenicity.
• CBACs hold broad potential for developing new therapeutic modalities for various diseases driven by membrane protein dysregulation.