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Updated: Dec 31, 2025
Peptide-based Identification of Functional Motifs and their Binding Partners
Published on: June 30, 2013
Identification of folate receptor α (FRα) binding oligopeptides and their evaluation for targeted virotherapy
Sarah L Hulin-Curtis1, James A Davies1, Davor Nestić2
1Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
Abstract:
Oncolytic virotherapies (OV) based on human adenoviral (HAdV) vectors hold significant promise for the treatment of advanced ovarian cancers where local, intraperitoneal delivery to tumour metastases is feasible, bypassing many complexities associated with intravascular delivery. The efficacy of HAdV-C5-based OV is hampered by a lack of tumour selectivity, where the primary receptor, hCAR, is commonly downregulated during malignant transformation. Conversely, folate receptor alpha (FRα) is highly expressed on ovarian cancer cells, providing a compelling target for tumour selective delivery of virotherapies. Here, we identify high-affinity FRα-binding oligopeptides for genetic incorporation into HAdV-C5 vectors. Biopanning identified a 12-mer linear peptide, DWSSWVYRDPQT, and two 7-mer cysteine-constrained peptides, CIGNSNTLC and CTVRTSAEC that bound FRα in the context of the phage particle. Synthesised lead peptide, CTVRTSAEC, bound specifically to FRα and could be competitively inhibited with folic acid. To assess the capacity of the elucidated FRα-binding oligopeptides to target OV to FRα, we genetically incorporated the peptides into the HAdV-C5 fiber-knob HI loop including in vectors genetically ablated for hCAR interactions. Unfortunately, the recombinant vectors failed to efficiently target transduction via FRα due to defective intracellular trafficking following entry via FRα, indicating that whilst the peptides identified may have potential for applications for targeted drug delivery, they require additional refinement for targeted virotherapy applications.
Insights
Researchers explored targeting ovarian cancer with oncolytic adenoviruses (OV) using folate receptor alpha (FRα). While FRα-binding peptides were identified, the engineered viruses showed defective intracellular trafficking, limiting their virotherapy potential.
Area of Science:
- Oncolytic Virotherapy
- Cancer Therapeutics
- Molecular Targeting
Background:
- Oncolytic virotherapies (OV) using human adenoviral (HAdV) vectors show promise for ovarian cancer, but lack tumor selectivity.
- The primary HAdV receptor, hCAR, is often downregulated in ovarian cancers.
- Folate receptor alpha (FRα) is highly expressed on ovarian cancer cells, presenting a target for selective OV delivery.
Purpose of the Study:
- To identify and genetically incorporate FRα-binding peptides into HAdV-C5 vectors for targeted ovarian cancer virotherapy.
- To evaluate the efficacy of FRα-targeted HAdV-C5 vectors in delivering OV to FRα-expressing ovarian cancer cells.
Main Methods:
- Biopanning was used to identify high-affinity FRα-binding oligopeptides.
- Identified peptides were genetically incorporated into the HAdV-C5 fiber-knob HI loop, including in vectors lacking hCAR interaction.
- The targeting and transduction capabilities of the engineered vectors were assessed.
Main Results:
- High-affinity FRα-binding peptides (e.g., CTVRTSAEC) were identified and synthesized.
- Engineered HAdV-C5 vectors incorporating these peptides failed to efficiently target transduction via FRα.
- Defective intracellular trafficking following FRα-mediated entry was observed.
Conclusions:
- While FRα-binding peptides show potential for targeted drug delivery, they require further refinement for effective oncolytic virotherapy applications.
- Targeted delivery via FRα using current peptide modifications is insufficient for successful adenoviral virotherapy due to intracellular trafficking issues.
