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A comparative study of synthetic and semisynthetic approaches for ligating the epidermal growth factor to a bivalent
Anna Lena Gell1, Nadja Groysbeck1, Christian F W Becker1
1Faculty of Chemistry, Institute of Biological Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
Abstract:
A prominent target of monoclonal antibodies as targeted therapies for cancer is the epidermal growth factor receptor, which is overexpressed on the surface of various cancer cell types. Its natural binder, the epidermal growth factor (EGF), is a 53 amino acid polypeptide. Anticancer synthetic targeted immune system engagers (ISErs) comprising two 'binder' peptides, which are attached to a scaffold conveying immune stimulating 'effector' properties, via monodisperse polyethylene glycol chains. So far, preparation of ISErs has been limited to the use of small peptides (8-20 amino acids) as binding functionalities, and they have been entirely synthesized by solid phase peptide synthesis. Here, we describe a synthetic and a semisynthetic approach for the preparation of an ISEr bearing two murine EGF molecules as binding entities (ISEr-EGF2 ). EGF was either synthesized in segments by solid phase peptide synthesis or expressed recombinantly and ligated to the scaffold by native chemical ligation. We report the successful generation of synthetic and semisynthetic ISEr-EGF2 as well as several challenges encountered during the synthesis and ligations. We demonstrate the application of native chemical ligation for the design of larger ISEr constructs, facilitating new objectives for the coupling of small binder peptides and larger proteins to multivalent ISEr scaffolds. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Insights
Researchers developed new methods to create larger targeted cancer therapies. These immune system engagers (ISErs) use epidermal growth factor (EGF) to target cancer cells, offering a promising advancement in cancer treatment.
Area of Science:
- Biochemistry
- Immunology
- Oncology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in cancer therapy.
- Current targeted therapies often use small peptides, limiting construct size and complexity.
- Immune system engagers (ISErs) combine targeting and immune-stimulating properties.
Purpose of the Study:
- To develop synthetic and semisynthetic methods for preparing larger ISErs.
- To create an ISEr utilizing the full epidermal growth factor (EGF) molecule as a binder.
- To explore the application of native chemical ligation for constructing complex ISEr scaffolds.
Main Methods:
- Segmental solid-phase peptide synthesis of EGF.
- Recombinant expression of EGF.
- Native chemical ligation to attach EGF to a scaffold.
- Preparation of a bivalent EGF-based ISEr (ISEr-EGF2).
Main Results:
- Successful generation of synthetic and semisynthetic ISEr-EGF2.
- Demonstrated the feasibility of using native chemical ligation for larger ISEr constructs.
- Identified challenges in synthesis and ligation processes.
Conclusions:
- Native chemical ligation is a viable method for creating larger, more complex ISEr constructs.
- This approach expands possibilities for coupling larger proteins or multiple small peptides to ISEr scaffolds.
- Enables new objectives for targeted cancer immune therapies.
