NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands

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.