Targeting the EphA4 receptor in the nervous system with biologically active peptides

Murai, Keith K.; Nguyen, Louis N.; Koolpe, Mitchell; McLennan, Rebecca; Krull, Catherine E.; Pasquale, Elena B.

doi:10.1016/j.mcn.2003.08.006

Cited by 93 publications

(124 citation statements)

References 37 publications

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“…Competition experiments and sequence alignments suggest that all the peptides, with the possible exception of one, target the ephrin-binding site of each Eph receptor, even though the entire EphB ectodomain was used for panning. This is consistent with previous results with peptides that bind to EphA receptors (20,21) and with the propensity of phage-displayed peptides to target the binding interfaces of proteins (28 -30). The EphB-binding peptides probably mimic the continuous sequence of the ephrin-B G-H loop, which is 15 amino acids long.…”

Section: Fig 5 Peptides As Ephb Receptor-targeting Agentssupporting

confidence: 93%

“…However, interactions between Eph receptors and ephrins belonging to the same class are highly promiscuous (1,18,19). Nevertheless, several 12-amino acid long peptides identified by phage display bind selectively to one or few Eph receptors of the A class (20,21). These peptides have some sequence similarity with the 15-amino acid long G-H loop of the ephrins, which is the main region mediating high affinity binding of the ephrins to the Eph receptors (22).…”

mentioning

confidence: 99%

“…These peptides have additional distinctive sequence features that presumably confer their binding selectivity for specific EphA receptors. Importantly, micromolar concentrations of peptides that bind to EphA2 and EphA4 inhibit ephrin binding to these receptors (20,21). Interestingly, the EphA4-binding peptides are antagonists that inhibit receptor activation by ephrins (21), whereas the EphA2-binding peptides behave as ephrin mimics and promote EphA2 activation and downstream signaling (20).…”

mentioning

confidence: 99%

“…Importantly, micromolar concentrations of peptides that bind to EphA2 and EphA4 inhibit ephrin binding to these receptors (20,21). Interestingly, the EphA4-binding peptides are antagonists that inhibit receptor activation by ephrins (21), whereas the EphA2-binding peptides behave as ephrin mimics and promote EphA2 activation and downstream signaling (20). 1 The antagonistic peptides likely function by preventing ephrin-dependent Eph receptor clustering and transphosphorylation, which are necessary steps to activate downstream signaling pathways (1,2).…”

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confidence: 99%

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EphB Receptor-binding Peptides Identified by Phage Display Enable Design of an Antagonist with Ephrin-like Affinity

Koolpe

Burgess

Dail

et al. 2005

Journal of Biological Chemistry

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133

157

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The Eph receptor tyrosine kinases are overexpressed in many pathologic tissues and have therefore emerged as promising drug target candidates. However, there are few molecules available that can selectively bind to a single Eph receptor and not other members of this large receptor family. Here we report the identification by phage display of peptides that bind selectively to different receptors of the EphB class, including EphB1, EphB2, and EphB4. Peptides with the same EphB receptor specificity compete with each other for binding, suggesting that they have partially overlapping binding sites. In addition, several of the peptides contain amino acid motifs found in the G-H loop of the ephrin-B ligands, which is the region that mediates high-affinity interaction with the EphB receptors. Consistent with targeting the ephrin-binding site, the higher affinity peptides antagonize ephrin binding to the EphB receptors. We also designed an optimized EphB4-binding peptide with affinity comparable with that of the natural ligand, ephrin-B2. These peptides should be useful as selective inhibitors of the pathological activities of EphB receptors and as targeting agents for imaging probes and therapeutic drugs.

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Section: Fig 5 Peptides As Ephb Receptor-targeting Agentssupporting

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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EphB Receptor-binding Peptides Identified by Phage Display Enable Design of an Antagonist with Ephrin-like Affinity

Koolpe

Burgess

Dail

et al. 2005

Journal of Biological Chemistry

Self Cite

133

157

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“…2,6,8 Among the EphA4-targeting peptides identified using phage display screens and other strategies, the linear dodecameric KYL (KYLPYWPVLSSL) was initially considered the most promising. 2,9 Although the ephrin ligands promiscuously bind multiple Eph receptors, KYL binds only to EphA4. Despite its modest (∼1 μM) binding affinity, KYL has been instrumental not only as a research tool but also in demonstrating the potential therapeutic value of pharmacologically inhibiting EphA4 in in vitro and in vivo models of ALS, Alzheimer's disease, spinal cord injury, and breast cancer.…”

mentioning

confidence: 99%

Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability

Olson

Lechtenberg

Zhao

et al. 2016

ACS Med. Chem. Lett.

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EphA4 is a receptor tyrosine kinase with a critical role in repulsive axon guidance and synaptic function. However, aberrant EphA4 activity can inhibit neural repair after injury and exacerbate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's. We previously identified the cyclic peptide APY-d2 (APYCVYRβASWSC-NH 2 , containing a disulfide bond) as a potent and selective EphA4 antagonist. However, APY-d2 lacks sufficient plasma stability to be useful for EphA4 inhibition in vivo through peripheral administration. Using structure−activity relationship studies, we show that protecting the peptide N-terminus from proteolytic degradation dramatically increases the persistence of the active peptide in plasma and that a positively charged peptide N-terminus is essential for high EphA4 binding affinity. Among several improved APY-d2 derivatives, the cyclic peptides APY-d3 (βAPYCVYRβASWSC-NH 2 ) and APY-d4 (βAPYCVYRβAEWEC-NH 2 ) combine high stability in plasma and cerebrospinal fluid with slightly enhanced potency. These properties make them valuable research tools and leads toward development of therapeutics for neurological diseases.

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Training Neural Stem Cells on Functional Collagen Scaffolds for Severe Spinal Cord Injury Repair

Liu

Zhao

et al. 2016

Adv Funct Materials

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Neural stem cells (NSCs) transplantation is regarded as a promising therapeutic strategy to treat severe spinal cord injury (SCI) by compensating the neuronal loss. However, significant challenges including long‐term survival, directed neuronal differentiation, and functional integration of the transplanted NSCs and their progenies within the host spinal cord are yet to be solved. In this study, NSCs are trained on differently modified collagen scaffolds to increase their neuronal differentiation rate when cultured under the simulated SCI microenvironment. Then, a functional scaffold is screened out, on which the cultured NSCs show high neuronal differentiation rate and generate both sensory and motor mature neurons. Subsequently, that NSC seeded functional scaffold is transplanted into a rat severe SCI model. The results show that higher endogenous neurogenesis efficiency as well as in vivo survival and neuronal differentiation rate of the grafted NSCs are observed. Moreover, both sensory and motor neurons are found to be differentiated from the grafted NSCs in the lesion site and those newly generated neurons can functionally interact with each other and the host neurons. Taken together, the in vitro training systems for modulating the differentiation profiles of NSCs are instructive and exhibit strong potentials for SCI treatments.

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Targeting the EphA4 receptor in the nervous system with biologically active peptides

Cited by 93 publications

References 37 publications

EphB Receptor-binding Peptides Identified by Phage Display Enable Design of an Antagonist with Ephrin-like Affinity

EphB Receptor-binding Peptides Identified by Phage Display Enable Design of an Antagonist with Ephrin-like Affinity

Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability

Training Neural Stem Cells on Functional Collagen Scaffolds for Severe Spinal Cord Injury Repair

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