EGFR-Binding Peptides: From Computational Design towards Tumor-Targeting of Adeno-Associated Virus Capsids

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• The epidermal growth factor receptor (EGFR) is a key driver in numerous solid tumor progressions.
• Targeting EGFR is a validated strategy for cancer therapy.
• Developing novel delivery systems for therapeutic payloads is crucial.

Purpose of the Study:

• To computationally design novel peptides that bind to the EGFR dimerization interface.
• To engineer recombinant adeno-associated viruses (rAAV) displaying these peptides for targeted delivery.
• To evaluate the efficacy of these peptide-modified viral vectors in targeting EGFR-overexpressing tumors.

Main Methods:

• De novo computational design of EGFR-binding peptides.
• Chemical synthesis and characterization of designed peptides.
• Genetic loop insertion of peptides into rAAV capsid proteins.
• In vitro cell targeting assays with EGFR-overexpressing lines.
• In vivo tissue distribution and tumor specificity analysis using chicken egg chorioallantoic membrane (CAM) assays.

Main Results:

• Two novel peptides and a reference peptide (EDA) were successfully synthesized and demonstrated EGFR binding.
• rAAV vectors displaying these peptides effectively targeted EGFR-overexpressing tumor cell lines.
• CAM assays revealed specific tissue distribution and tumor targeting of the modified viral vectors.
• Complex correlations were observed between peptide-vector targeting and cellular/in ovo delivery.

Conclusions:

• Computational peptide design coupled with rational viral capsid modification is a viable strategy for targeted viral vector delivery.
• This approach shows promise for advancing viral vector applications, particularly in suicide gene therapy for cancer.
• The study opens new avenues for developing targeted therapies against EGFR-driven cancers.