Rational Development of a Peptide Antagonist for EphA4, a Cell-Surface Receptor Linked to Neurodegeneration
Erika Olson
Postdoctoral Researcher, Harvard Medical School
EphA4 is a cell-surface receptor tyrosine kinase primarily expressed in the central nervous system in regions of frequent remodeling such as the hippocampus and cerebral cortex. It is a member of a large family of transmembrane receptor tyrosine kinases that are critical for tissue patterning as well as neural and immune function. Acute neural trauma has been shown to increase expression levels of EphA4 in humans and disease severity correlates with increased EphA4 expression in amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) patients, while inhibition of EphA4 activation has been shown to slow neuronal death in mouse models of ALS and promote reinnervation in spinal cord injury models. The natural ligands of EphA4, the ephrins, bind promiscuously within the Eph receptor family and show little potential for development into selective inhibitors. Several peptides identified by phage display were shown to bind selectively to the ligand-binding domain of EphA4 and competitively inhibit ligand binding, phosphorylation, and signaling pathway activation. Using crystallographic data to guide mutation to natural and non-natural amino acids, we have developed a peptide with IC50 of ~20 nM and high stability to serum proteases. We found that this peptide inhibits the neuronal recession caused by EphA4 activation in primary culture neurons.
Erika Olson received her Ph.D. in Chemical Biology from The Scripps Research Institute (La Jolla, CA) in May 2018. Her doctoral work with Professor Philip Dawson, performed in collaboration with Drs. Pasquale and Riedl at SBPMDI, focused on the rational development and biophysical analysis of medically relevant peptides. She has co-authored three publications and two patents on her doctoral work to date. She is currently working as a postdoctoral researcher with Professor Pamela Silver at Harvard Medical School (Boston, MA) on building a systematic functional understanding of how viruses inhibit intracellular innate immunity and using this understanding to develop improved strategies for mammalian genetic engineering.