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Circular Bivalent Aptamer Chimeras Leveraging LDLR-Mediated Lysosomal Shuttling for Targeted Protein Degradation
Ningyi Li1,2, Zhenzhen Guo3, Ruirui Zhang1,2
1State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, School of Convergence Medicine, Zhengzhou University, Zhengzhou450052, China.
Abstract:
Dysregulation of membrane proteins underlies various human diseases, with their overexpression or mutation frequently being associated with cancer progression. Although targeted protein degradation technologies such as proteolysis-targeting chimeras and lysosome-targeting chimeras represent promising therapeutic strategies, their efficacy is often limited by scarce targeting ligands, complex preparation procedures, potential immunogenicity, and other factors. Here, we present a lysosome-targeting degradation platform based on circular bivalent aptamer chimeras (CBACs), which simultaneously engage the lysosomal shuttle receptor LDLR and target membrane proteins. Leveraging the natural LDLR recycling pathway, CBAC triggers receptor-mediated endocytosis and lysosomal degradation while recycling the LDLR. We demonstrate efficient and selective degradation of two cancer-therapeutically relevant membrane proteins, c-Met and PTK7, in multiple cancer cells, leading to apoptosis and reduced invasion and migration. Given its modular design and reliance on endogenous trafficking machinery, this platform holds broad potential for the degradation of diverse membrane proteins and could facilitate the development of new therapeutic modalities.
Insights
Scientists developed a new platform using circular bivalent aptamer chimeras (CBACs) to degrade disease-associated membrane proteins. This targeted protein degradation approach shows promise for cancer therapy by selectively eliminating harmful proteins.
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.
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