Eph receptor tyrosine kinases and ephrin ligands constitute an important cell communication
system that controls development, tissue homeostasis and many pathological processes. Various
Eph receptors/ephrins are present in essentially all cell types and their expression is often dysregulated
by injury and disease. Thus, the 14 Eph receptors are attracting increasing attention as a major class of
potential drug targets. In particular, agents that bind to the extracellular ephrin-binding pocket of these
receptors show promise for medical applications. This pocket comprises a broad and shallow groove
surrounded by several flexible loops, which makes peptides particularly suitable to target it with high affinity and selectivity.
Accordingly, a number of peptides that bind to Eph receptors with micromolar affinity have been identified using
phage display and other approaches. These peptides are generally antagonists that inhibit ephrin binding and Eph receptor/
ephrin signaling, but some are agonists mimicking ephrin-induced Eph receptor activation. Importantly, some of the
peptides are exquisitely selective for single Eph receptors. Most identified peptides are linear, but recently the considerable
advantages of cyclic scaffolds have been recognized, particularly in light of potential optimization towards drug
leads. To date, peptide improvements have yielded derivatives with low nanomolar Eph receptor binding affinity, high resistance
to plasma proteases and/or long in vivo half-life, exemplifying the merits of peptides for Eph receptor targeting.
Besides their modulation of Eph receptor/ephrin function, peptides can also serve to deliver conjugated imaging and
therapeutic agents or various types of nanoparticles to tumors and other diseased tissues presenting target Eph receptors.