Dual-targeting fluorous peptide proteolysis-targeting chimeras for cancer therapy
Guangyu Rong1, Yuhan Li2, Fang Zhu2
1Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
Abstract:
Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for degrading disease-causing proteins. Simultaneous degradation of two oncogenic proteins by PROTACs can yield synergistic therapeutic effects. Here, we developed a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) that leverages supramolecular self-assembly for cancer therapy. By conjugating PD-L1- and Bcl-xL-binding peptides to fluorous tags, we generated carrier-free nanoparticles that enter cells via macropinocytosis and achieve efficient endosomal escape, mediating simultaneous degradation of both extracellular PD-L1 and cytosolic Bcl-xL through the ubiquitin-proteasome system. Our results demonstrate that DFP-PROTAC coordinately restores antitumor immunity and apoptotic sensitivity while achieving superior antitumor efficacy with excellent biocompatibility in B16-F10 melanoma-bearing mice, highlighting its therapeutic potential for cancer treatment. This modular fluorous platform offers a versatile strategy for degrading multiple protein targets in the treatment of various diseases.
Insights
This study introduces a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) for cancer therapy. This innovative approach simultaneously degrades two oncogenic proteins, enhancing therapeutic effects and demonstrating superior antitumor efficacy.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Proteolysis-targeting chimeras (PROTACs) are effective for targeted protein degradation.
- Simultaneous degradation of multiple oncogenic proteins can lead to synergistic therapeutic outcomes.
- Developing novel PROTAC delivery systems is crucial for enhancing cancer treatment efficacy.
Purpose of the Study:
- To develop a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) for simultaneous degradation of PD-L1 and Bcl-xL.
- To investigate the self-assembly properties and cellular uptake mechanisms of the DFP-PROTAC.
- To evaluate the in vivo antitumor efficacy and biocompatibility of the DFP-PROTAC in a melanoma mouse model.
Main Methods:
- Conjugation of PD-L1 and Bcl-xL binding peptides to fluorous tags to create DFP-PROTAC.
- Characterization of carrier-free nanoparticles formed by supramolecular self-assembly.
- Assessment of cellular uptake via macropinocytosis and endosomal escape.
- Evaluation of simultaneous protein degradation via the ubiquitin-proteasome system.
- In vivo studies in B16-F10 melanoma-bearing mice to assess antitumor efficacy and biocompatibility.
Main Results:
- DFP-PROTAC self-assembles into carrier-free nanoparticles with efficient cellular entry and endosomal escape.
- Simultaneous degradation of extracellular PD-L1 and cytosolic Bcl-xL was achieved.
- Restoration of antitumor immunity and apoptotic sensitivity was observed.
- Superior antitumor efficacy and excellent biocompatibility were demonstrated in vivo.
- The fluorous platform showed versatility for targeting multiple proteins.
Conclusions:
- DFP-PROTAC represents a novel strategy for synergistic cancer therapy through simultaneous dual-protein degradation.
- The fluorous self-assembly platform offers a versatile and effective approach for targeted protein degradation in cancer treatment.
- This technology holds significant therapeutic potential for various diseases driven by multiple protein targets.
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