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

Authors

Yan Shi, University of South FloridaFollow
Sridevi Challa, H. Lee Moffitt Cancer Center and Research Institute
Peng Sang, University of South FloridaFollow
Fengyu She, University of South Florida
Chunpu Li, Shanghai University of Traditional Chinese Medicine
Geoffrey M. Gray, University of South Florida
Alekhya Nimmagadda, University of South Florida
Peng Teng, University of South Florida
Timothy Odom, University of South Florida
Yan Wang, Shanghai University of Traditional Chinese Medicine
Arjan van der Vaart, University of South FloridaFollow
Qi Li, Shanghai University of Traditional Chinese Medicine and Pharmacology
Jianfeng Cai, University of South FloridaFollow

Document Type

Article

Publication Date

2017

Digital Object Identifier (DOI)

https://doi.org/10.1021/acs.jmedchem.7b01280

Abstract

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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Journal of Medicinal Chemistry, v. 60, issue 22, p. 9290-9298

Scholar Commons Citation

Shi, Yan; Challa, Sridevi; Sang, Peng; She, Fengyu; Li, Chunpu; Gray, Geoffrey M.; Nimmagadda, Alekhya; Teng, Peng; Odom, Timothy; Wang, Yan; Vaart, Arjan van der; Li, Qi; and Cai, Jianfeng, "One-Bead–Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2" (2017). Chemistry Faculty Publications. 190.
https://digitalcommons.usf.edu/chm_facpub/190