Artificial Nucleic Acid Tractor-Directed Simultaneous Depletion of Oncogenic Membrane Proteins Without Hijacking Proteolysis-Specific Actuator
CCS CHEMISTRY(2024)
Abstract
Targeted protein degradation (TPD) is an emerging tool for degrading proteins of interest, which affords an attractive modality for cancer therapy. However, the present TPD technologies must engage a proteolysis-specific actuator to initiate degradation of targeted proteins in the proteasome or lysosome. Herein, we report an artificial tractor that can induce endocytosis-mediated protein depletion without hijacking a proteolysis-specific actuator. In this de-sign, bispecific aptamer chimeras (BSACs) are estab-lished, which can bridge human epidermal growth factor receptor 2 (ErbB-2), an important biomarker in a common important biomarker in cancer, with membrane proteins of interest. Taking advantage of the property of aptamer-induced endocytosis and digestion of ErbB-2, another membrane protein is translocated into the lysosome in a hitchhike-like manner, resulting in lysosomal proteolysis along with ErbB-2. This strategy frees the TPD from the fundamental limitation of proteolysis-specific actua-tor and allows simultaneous regulation of the quantity and function of two oncogenic receptors in a cell-type-specific manner, expanding the application scope of TPD-based therapeutics.
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Key words
targeted protein degradation,aptamer,epidermal growth factor receptor 2,lysosome,membrane proteins,cancer therapy
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