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One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2
Yan Shi1, Sridevi Challa2, Peng Sang1
1Department of Chemistry, University of South Florida , 4202 E. Fowler Avenue, Tampa, Florida 33620, United States.
Journal of Medicinal Chemistry
|November 8, 2017
Summary
Researchers developed a novel cyclic peptidomimetic library for identifying molecular ligands. This approach successfully discovered a compound that binds and antagonizes the EphA2 receptor tyrosine kinase.
Area of Science:
- Chemical Biology
- Biomedical Sciences
- Drug Discovery
Background:
- Identifying molecular ligands for peptides and proteins is crucial but challenging.
- Existing cyclic peptidomimetic libraries are limited, hindering ligand discovery for protein targets.
Purpose of the Study:
- To develop a novel one-bead-two-compound (OBTC) combinatorial library for macrocyclic peptidomimetics.
- To explore the utility of this library for identifying specific protein-binding ligands.
Main Methods:
- Synthesized a library of macrocyclic γ-AApeptides using an OBTC approach.
- Employed orthogonal Dde-protected peptide tags for coding.
- Utilized a thioether linkage for library construction.
- Screened the library against the receptor tyrosine kinase EphA2.
Main Results:
- Successfully generated a novel macrocyclic peptidomimetic library.
- Discovered a lead compound with high affinity (Kd = 81 nM) for EphA2.
- Demonstrated potent antagonism of EphA2-mediated signaling by the lead compound.
Conclusions:
- The developed OBTC library platform is effective for macrocyclic peptidomimetic ligand discovery.
- This approach offers a new strategy for biomacromolecular surface recognition and function modulation.
- The identified EphA2 ligand demonstrates therapeutic potential.
