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Published on: January 26, 2024
Targeting EphA2-Sam and Its Interactome: Design and Evaluation of Helical Peptides Enriched in Charged Residues
Flavia A Mercurio1, Daniela Marasco1,2, Concetta Di Natale3
1Institute of Biostructures and Bioimaging, National Research Council, Via Mezzocannone 16, 80134, Naples, Italy.
Abstract:
The EphA2 receptor controls diverse physiological and pathological conditions and its levels are often upregulated in cancer. Targeting receptor overexpression, through modulation of endocytosis and consequent degradation, appears to be an appealing strategy for attacking tumor malignancy. In this scenario, the Sam domain of EphA2 plays a pivotal role because it is the site where protein regulators of endocytosis and stability are recruited by means of heterotypic Sam-Sam interactions. Because EphA2-Sam heterotypic complexes are largely based on electrostatic contacts, we have investigated the possibility of attacking these interactions with helical peptides enriched in charged residues. Several peptide sequences with high predicted helical propensities were designed, and detailed conformational analyses were conducted by diverse techniques including NMR, CD, and molecular dynamics (MD) simulations. Interaction studies were also performed by NMR, surface plasmon resonance (SPR), and microscale thermophoresis (MST) and led to the identification of two peptides capable of binding to the first Sam domain of Odin. These molecules represent early candidates for the generation of efficient Sam domain binders and antagonists of Sam-Sam interactions involving EphA2.
Insights
Researchers designed charged peptides to disrupt EphA2 receptor interactions crucial for cancer progression. These peptides show potential for developing new cancer therapies by targeting tumor malignancy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- The EphA2 receptor is upregulated in cancer, making it a target for anti-tumor strategies.
- Modulating EphA2 receptor endocytosis and degradation is a promising approach to combat cancer.
- The Sam domain of EphA2 is critical for recruiting protein regulators involved in endocytosis and stability via heterotypic Sam-Sam interactions.
Purpose of the Study:
- To investigate the disruption of EphA2-Sam heterotypic interactions using charged helical peptides.
- To identify novel peptide-based antagonists for Sam-Sam interactions involving EphA2.
Main Methods:
- Design of helical peptides enriched in charged residues.
- Conformational analysis using Nuclear Magnetic Resonance (NMR), Circular Dichroism (CD), and Molecular Dynamics (MD) simulations.
- Interaction studies employing NMR, Surface Plasmon Resonance (SPR), and Microscale Thermophoresis (MST).
Main Results:
- Identification of two peptides with high helical propensities and predicted electrostatic interactions.
- Demonstration of peptide binding to the first Sam domain of Odin.
- Validation of peptides as potential antagonists of Sam-Sam interactions.
Conclusions:
- Charged helical peptides can effectively target and disrupt EphA2-Sam heterotypic interactions.
- These peptides represent promising lead compounds for developing novel cancer therapeutics.
- Targeting Sam-Sam interactions offers a new avenue for inhibiting tumor malignancy.
