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novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to
crosslink the side chains of the two Cys at (i, i+4) positions. By this way, we successfully induced the formation
of and stabilized a productive α-helical conformation of PMI - a dual-specificity peptide antagonist of MDM2
and MDMX, enabling it to traverse the cell membrane and kill tumor cells by reactivating the p53 pathway.
This stapling functionally rescued PMI that, on its own, failed to activate p53 because of its poor membrane
permeability and susceptibility to proteolytic degradation. Taken together, this work not only illustrates that
the restoration of p53 is a potentially feasible program for HCC therapy, but promises an important new tool
for peptide drug discovery and development for a variety of human diseases.

DECLARATIONS
Authors’ contributions
Did experiments: Jiang W, Jin L
Designed this work: Liu M, Hou P, He WX
Wrote this paper: Hou P, He WX
Revised the manuscripts: All authors

Availability of data and materials
The patient mRNA data was from TCGA. All experimental data did by the authors listed in this paper.

Financial support and sponsorship
This work was supported by the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong
University (XJTU1AF-CRF-2017-003) to Hou P and He WX.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2019.

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