2021
DOI: 10.1021/acs.jmedchem.1c00608
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NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands

Abstract: In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosi… Show more

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Cited by 7 publications
(29 citation statements)
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“…Initial screen and subsequent structure-activity relationships studies lead to agent 123C4 ( Table 1 ), with an affinity for the isolated EphA4 ligand-binding domain (LBD) of ∼400 nM by isothermal titration calorimetry (ITC) ( Wu et al., 2013 , 2017 ). In follow-up studies, we derived a new combinatorial library based on the critical N-terminal aliphatic amine of 123C4 (a common feature also of antagonistic peptides) ( Olson et al., 2016 ; Wu et al., 2013 ) and exploited our previous experience with the f HTS by NMR ( Baggio et al., 2017 ), we rapidly identified a new hit molecule ( Baggio et al., 2021 ). We also developed an efficient strategy to anticipate if ligand binding would induce changes in EphA4 conformation that are more compatible with agonist versus antagonist binding ( Baggio et al., 2021 ).…”
Section: Resultsmentioning
confidence: 99%
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“…Initial screen and subsequent structure-activity relationships studies lead to agent 123C4 ( Table 1 ), with an affinity for the isolated EphA4 ligand-binding domain (LBD) of ∼400 nM by isothermal titration calorimetry (ITC) ( Wu et al., 2013 , 2017 ). In follow-up studies, we derived a new combinatorial library based on the critical N-terminal aliphatic amine of 123C4 (a common feature also of antagonistic peptides) ( Olson et al., 2016 ; Wu et al., 2013 ) and exploited our previous experience with the f HTS by NMR ( Baggio et al., 2017 ), we rapidly identified a new hit molecule ( Baggio et al., 2021 ). We also developed an efficient strategy to anticipate if ligand binding would induce changes in EphA4 conformation that are more compatible with agonist versus antagonist binding ( Baggio et al., 2021 ).…”
Section: Resultsmentioning
confidence: 99%
“…In follow-up studies, we derived a new combinatorial library based on the critical N-terminal aliphatic amine of 123C4 (a common feature also of antagonistic peptides) ( Olson et al., 2016 ; Wu et al., 2013 ) and exploited our previous experience with the f HTS by NMR ( Baggio et al., 2017 ), we rapidly identified a new hit molecule ( Baggio et al., 2021 ). We also developed an efficient strategy to anticipate if ligand binding would induce changes in EphA4 conformation that are more compatible with agonist versus antagonist binding ( Baggio et al., 2021 ). This was accomplished by protein NMR using EphA4-LBD that is uniformly labeled with 13 C ε -methionine ( Wu et al., 2017 ).…”
Section: Resultsmentioning
confidence: 99%
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