Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells

Wu, Bainan; Wang, Si; De, Surya K.; Barile, Elisa; Quinn, Bridget A.; Zharkikh, Irina; Purves, Angela; Stebbins, John L.; Oshima, Robert G.; Fisher, Paul B.; Pellecchia, Maurizio

doi:10.1016/j.chembiol.2015.06.011

Cited by 30 publications

(66 citation statements)

References 41 publications

(91 reference statements)

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“…Starting from compound 22, we sought to modify its N- and C- terminal ends to increase its binding affinity for EphA4-LBD. Moreover, our working hypothesis was that replacement of both termini with non-natural amino acids could result in increased resistance to proteases in vivo and overall improved drug-likeness of the resulting peptide mimetic, based on our recent experience with other related systems (Wu et al, 2015b). Several structure-activity relationships emerged from the synthesized compounds (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Potent and Selective EphA4 Agonists for the Treatment of ALS

Kulinich

et al. 2017

Cell Chemical Biology

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Recent studies identified the receptor tyrosine kinase EphA4 as a disease-modifying gene that is critical for the progression of motor neuron degeneration. We report on the design and characterization of a family of EphA4 targeting agents that bind to its ligand binding domain with nanomolar affinity. The molecules exhibit excellent selectivity and display efficacy in a SOD1 mutant mouse model of ALS. Interestingly, the molecules appear to act as agonists for the receptor in certain surrogate cellular assays. While the exact mechanisms responsible for the therapeutic effect of the new agonists remain to be elucidated, we believe that the described agent represents both an invaluable pharmacological tool to further decipher the role of the EphA4 in ALS and potentially other human diseases, and a significant stepping stone for the development of novel treatments.

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Section: Resultsmentioning

confidence: 99%

Potent and Selective EphA4 Agonists for the Treatment of ALS

Kulinich

et al. 2017

Cell Chemical Biology

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“…To study the effects of multispecificity we selected two binder peptides (Figure ): the disulfide‐cyclized B9 targets integrin α 3 β 1 (also known as VLA‐3 or CD49c), whereas the linear 12‐mer peptide B59 targets ephrin A2 (EphA2) . The integrin α 3 ‐targeting binder peptide B9 was identified by use of a one‐bead‐one‐compound approach and developed as a peptidomimetic featuring several non‐proteinogenic residues and a disulfide bond between the N‐ and C‐terminal cysteine residues .…”

Section: Introductionmentioning

confidence: 99%

Synthetic Cancer‐Targeting Innate Immune Stimulators Give Insights into Avidity Effects

Conibear

Pötgens²,

Thewes

et al. 2018

ChemBioChem

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Multispecific and multivalent antibodies are seen as promising cancer therapeutics, and numerous antibody fragments and derivatives have been developed to exploit avidity effects that result in increased selectivity. Most of these multispecific and multivalent antibody strategies make use of recombinant expression of antigen-binding modules. In contrast, chemical synthesis and chemoselective ligations can be used to generate a variety of molecules with different numbers and combinations of binding moieties in a modular and homogeneous fashion. In this study we synthesized a series of targeted immune system engagers (ISErs) by using solid-phase peptide synthesis and chemoselective ligations. To explore avidity effects, we constructed molecules bearing different numbers and combinations of two "binder" peptides that target ephrin A2 and integrin α receptors and an "effector" peptide that binds to formyl peptide receptors and stimulates an immune response. We investigated various strategies for generating multivalent and multispecific targeted innate immune stimulators and studied their activities in terms of binding to cancer cells and stimulation of immune cells. This study gives insights into the influence that multivalency and receptor density have on avidity effects and is useful for the design of potential anticancer therapeutics.

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“…The serum stability of peptide-based drugs without modifications are, in general, less than 1 hour [31–34]. For instance, the half-life of glucagon-like protein-1 (GLP-1) is less than 5 minutes because dipeptidyl peptidase-4 (DPP-4) rapidly inactivates GLP-1 peptide in the circulation [32, 35].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, long-lasting peptide-based pro-apoptotic anti-cancer drugs are required to provide sufficient anti-cancer efficacy. Indeed, recent several reports showed that a long-lasting peptide conjugated to paclitaxel has the greatly improved efficacy on tumor growth [31, 36]. Thus, many efforts strived to design and search for the long-lasting peptide by modifying amino acid residues with unnatural residues or by conjugating AG10, fatty acids or albumin [37–40].…”

Section: Discussionmentioning

confidence: 99%

Necrosis-inducing peptide has the beneficial effect on killing tumor cells through neuropilin (NRP-1) targeting

et al. 2016

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The therapeutic efficacy of most anti-cancer drugs depends on their apoptosis-inducing abilities. Previously, we showed that a peptide containing the mitochondrial targeting domain (MTD) found in Noxa, a BH-3 only protein of Bcl-2 family, induces necrosis. Here, a fusion peptide of neuropilin-1 (NRP-1) targeting peptide and MTD peptide, designated tumor homing motif 17:MTD (TU17:MTD), was found to induce necrosis in cancer cells in vitro and to cause the regression of tumors when intravenously injected into mice bearing subcutaneous CT26 colorectal carcinoma tumors. The necrosis within tumor tissues was evident upon administering TU17:MTD. TU17:MTD penetrated into tumor cells by targeting to Neuropilin-1, which could be blocked by anti-NRP-1 antibody. The efficacy of TU17:MTD on tumor regression was higher than that of TU17:D(KLAKLAK)2, a fusion peptide of NRP-1 targeting peptide and a pro-apoptotic peptide. The necrotic cell death within tumor tissues was evident at day 1 after administering TU17:MTD systemically. Transplanted subcutaneous substantially reduced in size within two weeks and 5 days, respectively, with no apparent side effects. Together, these results propose that the pro-necrotic peptide MTD may present an alternative approach for development of targeted anti-cancer agents.

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Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells

Cited by 30 publications

References 41 publications

Potent and Selective EphA4 Agonists for the Treatment of ALS

Potent and Selective EphA4 Agonists for the Treatment of ALS

Synthetic Cancer‐Targeting Innate Immune Stimulators Give Insights into Avidity Effects

Necrosis-inducing peptide has the beneficial effect on killing tumor cells through neuropilin (NRP-1) targeting

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