Structure-Activity Relationship Analysis of Peptides Targeting the EphA2 Receptor

Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Biochemistry (Impact Factor: 3.02). 08/2010; 49(31):6687-95. DOI: 10.1021/bi1006223
Source: PubMed


The EphA2 receptor tyrosine kinase has emerged as a promising new therapeutic target in cancer because of its high level of expression in tumors. EphA2-specific antibodies have been used to deliver drugs and toxins to tumor cells, leading to inhibition of tumor growth and metastatic dissemination. We previously identified two related peptides, YSA and SWL, that selectively bind to the ligand-binding domain of EphA2 but not other Eph receptors and could therefore be useful as selective targeting agents. Here we characterize the two peptides and a series of derivatives. On the basis of systematic amino acid replacements, only five YSA residues appear to be critical for high-affinity receptor binding. Furthermore, a peptide comprising only the first five residues of YSA retains selectivity for EphA2. Similar to ephrin-A1, the physiological ligand for EphA2, both YSA and SWL activate EphA2 and inhibit downstream oncogenic signaling pathways in PC3 cancer cells. The two peptides and derivatives are quite stable in conditioned cell culture medium and show promise for delivering drugs and imaging agents to EphA2-expressing tumors.


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    • "Apart from antibody-based targeting, the synthetic YSA peptide can also efficiently direct various moieties to the EPHA2 receptor. Recently, Mitra et al (2010) elucidated functional properties of the YSA peptide as a specific binding molecule to EPHA2 with subsequent downstream signalling events in a prostate cancer cell line. Dickerson et al (2010) described the use of hydrogel nanoparticles coated with YSA peptide for the specific delivery of siRNA to EPHA2-expressing tumour cells, with the aim of enhancing chemosensitivity. "
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    • "Small peptides with affinities for the ephrin binding pocket of Eph receptors can inhibit ephrin binding to EphA2 [138], EphA4 [139], EphB2 [140], and EphB4 [140], and additional uncharacterized peptides show promise as Eph inhibitors [137]. EphA2 targeting peptides inhibit ephrin binding but also induce phosphorylation of EphA2 and modulate EphA2 signaling [141]. However, these peptides do not induce receptor degradation like full-length ephrinAs [138]. "
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    Pharmacological Research 10/2012; 67(1). DOI:10.1016/j.phrs.2012.10.008 · 4.41 Impact Factor
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    • "TNYL-RAW was synthesized by using solid phase Fmoc [N-(9-fluorenyl)methoxycarbonyl] chemistry on a 433A peptide synthesizer (Applied Biosystems, Foster City, CA) with a Tenta Gel S RAM resin, as described previously for other peptides [68]. Biotin was conjugated onto the ε–amino group of a Lys attached at the C terminus of TNYL-RAW through an aminohexanoic acid linker. "
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