Targeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis-related proteins. Aptamer-based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off-target effects due to the non-covalent interaction with target proteins. We here report the first design of a covalent aptamer-based autophagosome-tethering chimera (CApTEC) for the enhanced autophagic degradation of cell-surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL). This strategy relies on the site-specific incorporation of sulfonyl fluoride groups onto aptamers to enable the cross-linking with target proteins, coupled with the conjugation of an LC3 ligand to hijack the autophagy-lysosomal pathway for targeted protein degradation. The chemically engineered CApTECs exhibit enhanced on-target retention and improved structural stability. Our results also demonstrate that CApTECs achieve remarkably enhanced and prolonged degradation of membrane proteins compared to the non-covalent designs. Furthermore, the CApTEC targeting TfR1 is combined with 5-fluorouracil (5-FU) for synergistic tumor therapy in a mouse model, leading to substantial suppression of tumor growth. Our strategy may provide deep insights into the LC3-mdiated autophagic degradation, affording a modular and effective strategy for membrane protein degradation and precise therapeutic applications.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/anie.202425123 | DOI Listing |
FASEB J
January 2025
Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Nonunion is a significant complication in fracture management for surgeons. Salvianolic acid A (SAA), derived from the traditional Chinese plant Salviae miltiorrhizae Bunge (Danshen), exhibits notable anti-inflammatory and antioxidant properties. Although studies have demonstrated its ability to promote osteogenic differentiation, the exact mechanism of action remains unclear.
View Article and Find Full Text PDFCell Death Differ
January 2025
Translational Research Centre of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Ferroptosis is one of the cell death programs occurring after spinal cord injury (SCI) and is driven by iron-dependent phospholipid peroxidation. However, little is known about its underlying regulation mechanism. The present study demonstrated that lipid peroxidation was promoted in patients with SCI.
View Article and Find Full Text PDFNat Commun
January 2025
School of Life Sciences, BK21 FOUR KNU Creative BioRearch Group, Kyungpook National University, Daegu, South Korea.
Lysophagy eliminates damaged lysosomes and is crucial to cellular homeostasis; however, its underlying mechanisms are not entirely understood. We screen a ubiquitination-related compound library and determine that the substrate recognition component of the SCF-type E3 ubiquitin ligase complex, SCF(FBXO3), which is a critical lysophagy regulator. Inhibition of FBXO3 reduces lysophagy and lysophagic flux in response to L-leucyl-L-leucine methyl ester (LLOMe).
View Article and Find Full Text PDFJ Cachexia Sarcopenia Muscle
February 2025
Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, Jeollabuk-do, Republic of Korea.
Background: Sarcopenia, characterized by a gradual decline in skeletal muscle mass and function with age, significantly impacts both quality of life and mortality. Autophagy plays a crucial role in maintaining muscle health. There is growing interest in leveraging autophagy to mitigate muscle ageing effects.
View Article and Find Full Text PDFPLoS Pathog
January 2025
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
The intracellular protozoan Toxoplasma gondii manipulates host cell signaling to avoid targeting by autophagosomes and lysosomal degradation. Epidermal Growth Factor Receptor (EGFR) is a mediator of this survival strategy. However, EGFR expression is limited in the brain and retina, organs affected in toxoplasmosis.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!