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Hydrophobic CPP/HDO conjugates: a new frontier in oligonucleotide-warheaded PROTAC delivery.

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A new hydrophobic cell-penetrating peptide and heteroduplex oligonucleotide-conjugated Proteolysis-Targeting Chimera (CPP/HDO-PROTAC) enhances protein degradation. This novel approach overcomes delivery challenges for oligonucleotide-based PROTACs, showing promise for cancer therapy.

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Area of Science:

  • Biochemistry and Molecular Biology
  • Drug Delivery and Nanotechnology
  • Oncology and Cancer Therapeutics

Background:

  • Proteolysis-targeting chimeras (PROTACs) are a promising therapeutic strategy for targeted protein degradation, particularly in cancer treatment.
  • Oligonucleotide-based PROTACs face significant challenges in cellular delivery due to their anionic nature and chemical instability.
  • Existing transfection methods for oligonucleotide delivery are often inefficient and can be problematic for clinical applications.

Purpose of the Study:

  • To develop a novel delivery system for oligonucleotide-based PROTACs that enhances intracellular delivery and degradation efficiency.
  • To overcome the limitations associated with the anionic nature and chemical instability of oligonucleotide-based PROTACs.
  • To investigate the efficacy of a new hydrophobic cell-penetrating peptide (CPP) and heteroduplex oligonucleotide (HDO)-conjugated PROTAC (CPP/HDO-PROTAC) for targeted protein degradation.

Main Methods:

  • Design and synthesis of a novel CPP/HDO-PROTAC conjugate.
  • Evaluation of cellular uptake mechanism mediated by the hydrophobic CPP.
  • Assessment of RNase H-mediated release of decoy oligonucleotide-based PROTACs.
  • Measurement of estrogen receptor α (ERα) binding affinity and degradation efficiency in MCF-7 breast cancer cells.
  • Analysis of cell proliferation inhibition by the CPP/HDO-PROTAC.

Main Results:

  • The developed CPP/HDO-PROTAC demonstrated enhanced binding affinity to estrogen receptor α (ERα) compared to previous constructs.
  • Significant degradation of ERα was observed in MCF-7 human breast cancer cells treated with CPP/HDO-PROTAC.
  • CPP/HDO-PROTAC effectively inhibited cancer cell proliferation at a concentration of 10 μM.

Conclusions:

  • CPP/HDO-PROTAC represents a viable strategy for efficient intracellular delivery and activation of decoy oligonucleotide-based PROTACs.
  • This novel approach overcomes the limitations of traditional transfection methods for oligonucleotide-based therapeutics.
  • The findings support the potential clinical application of CPP/HDO-PROTAC for targeted protein degradation in diseases like cancer.