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.
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.
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