Open AccessNMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands
Author(s) -
Carlo Baggio,
Anna Kulinich,
Cassandra N. Dennys,
Rochelle Rodrigo,
Kathrin Meyer,
Iryna M. Ethell,
Maurizio Pellecchia
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00608
Subject(s) - chemistry , ligand (biochemistry) , amyotrophic lateral sclerosis , computational biology , receptor , stereochemistry , neuroscience , pharmacology , biochemistry , biology , medicine , disease , pathology
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 sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Together with preliminary in vivo pharmacology studies, the data form a strong foundation for the translation of these agents for the treatment of ALS and potentially other human diseases.