Rational Design of Right-handed Heterogeneous Peptidomimetics as Inhibitors of Protein–protein Interactions
Document Type
Article
Publication Date
2020
Digital Object Identifier (DOI)
https://doi.org/10.1021/acs.jmedchem.0c01638
Abstract
Peptidomimetics have gained great attention for their function as protein–protein interaction (PPI) inhibitors. Herein, we report the design and investigation of a series of right-handed helical heterogeneous 1:1 α/Sulfono-γ-AA peptides as unprecedented inhibitors for p53-MDM2 and p53-MDMX. The most potent helical heterogeneous 1:1 α/Sulfono-γ-AA peptides were shown to bind tightly to MDM2 and MDMX, with Kd of 19.3 and 66.8 nM, respectively. Circular dichroism spectra, 2D-NMR spectroscopy, and the computational simulations suggested that these helical sulfono-γ-AA peptides could mimic the critical side chains of p53 and disrupt p53/MDM2 PPI effectively. It was noted that these 1:1 α/Sulfono-γ-AA peptides were completely resistant to proteolytic degradation, boosting their potential for biomedical applications. Furthermore, effective cellular activity is achieved by the stapled 1:1 α/Sulfono-γ-AA peptides, evidenced by significantly enhanced p53 transcriptional activity and much more induced level of MDM2 and p21. The 1:1 α/Sulfono-γ-AA peptides could be an alternative strategy to antagonize a myriad of PPIs.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Journal of Medicinal Chemistry, v. 63, issue 21, p. 13187-13196
Scholar Commons Citation
Shi, Yan; Sang, Peng; Lu, Junhao; Higbee, Pirada; Chen, Lihong; Yang, Leixiang; Odom, Timothy; Daughdrill, Gary W.; Chen, Jiandong; and Cai, Jianfeng, "Rational Design of Right-handed Heterogeneous Peptidomimetics as Inhibitors of Protein–protein Interactions" (2020). Molecular Biosciences Faculty Publications. 168.
https://digitalcommons.usf.edu/bcm_facpub/168
