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Design and analysis of EphA2-SAM peptide ligands: A multi-disciplinary screening approach

Flavia Anna Mercurio¹, Concetta Di Natale², Luciano Pirone³

¹Institute of Biostructures and Bioimaging (CNR), Naples, Italy; InterUniversity Research Centre on Bioactive Peptides (CIRPEB), University of Naples Federico II, Naples, Italy.

Bioorganic Chemistry

|December 22, 2018

Abstract:

EphA2 receptor plays a critical and debatable function in cancer and is considered a target in drug discovery. Lately, there has been a growing interest in its cytosolic C-terminal SAM domain (EphA2-SAM) as it engages protein modulators of receptor endocytosis and stability. Interestingly, EphA2-SAM binds the SAM domain from the lipid phosphatase Ship2 (Ship2-SAM) mainly producing pro-oncogenic outcomes. In an attempt to discover novel inhibitors of the EphA2-SAM/Ship2-SAM complex with possible anticancer properties, we focused on the central region of Ship2-SAM (known as Mid-Loop interface) responsible for its binding to EphA2-SAM. Starting from the amino acid sequence of the Mid-Loop interface virtual peptide libraries were built through ad hoc inserted mutations with either l- or d- amino acids and screened against EphA2-SAM by docking techniques. A few virtual hits were synthesized and experimentally tested by a variety of direct and competition-type interaction assays relying on NMR (Nuclear Magnetic Resonance), SPR (Surface Plasmon Resonance), MST (Microscale Thermophoresis) techniques. These studies guided the discovery of an original EphA2-SAM ligand antagonist of its interaction with Ship2-SAM.

Keywords:

Cancer EphA2 MST NMR SAM domains SPR Ship2 Virtual screening

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