posted on 2020-11-03, 16:38authored byYan Shi, Peng Sang, Junhao Lu, Pirada Higbee, Lihong Chen, Leixiang Yang, Timothy Odom, Gary Daughdrill, Jiandong Chen, Jianfeng Cai
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.