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One-Bead-Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2.

Yan ShiSridevi ChallaPeng SangFengyu SheChunpu LiGeoffrey M GrayAlekhya NimmagaddaPeng TengTimothy OdomYan WangArjan van der VaartQi LiJianfeng Cai
Published in: Journal of medicinal chemistry (2017)
Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two-compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (Kd = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.
Keyphrases
  • tyrosine kinase
  • amino acid
  • high throughput
  • small molecule
  • epidermal growth factor receptor
  • hepatitis c virus
  • binding protein
  • human immunodeficiency virus
  • single cell
  • single molecule
  • hiv testing