The development of activatable lytic peptides for targeting triple negative breast cancer

Hui Zhao,Naihan Xu,Yanhong Jiang,Dongyuan Wang,Qisong Liu,Weihao Zheng,Dan Yang,Xuan Qin,Yuan Tian,Zigang Li

doi:10.1038/cddiscovery.2017.37

Abstract

Cytolytic peptides are an emerging class of promising cancer therapeutics shown to overcome drug resistance. They eliminate cancer cells via disruption of the phospholipid bilayer of cell membranes, a mechanism that differentiates it from traditional treatments. However, applications of lytic peptides via systematic administration are hampered by nonspecific toxicity. Here, we describe activatable, masked lytic peptides that are conjugated with anionic peptides via a cleavable linker sensitive to matrix metalloproteinases (Ac-w-βA-e8-XPLG*LAG-klUklUkklUklUk-NH2; lower case letters in the sequences represent D-amino-acids, U=Aib, α-aminoisobutyric acid, *cleavage site). The peptides were activated upon being introduced into the triple negative breast cancer cell line MDA-MB-231, which overexpresses secreted matrix metalloproteinases, to selectively cleave the peptide linker. Our results indicate that the activatable design could be applied to improve the targeting ability of lytic peptides.

Highlights

Cytolytic peptides typically have both cationic and amphiphilic properties, resulting in the lysis of cells in a nonspecific manner
To create effective short lytic peptides, we began with the proapoptotic peptide2.37 A D-Trp was attached to each peptide for concentration determination using a β-Ala as the linker
We showed that truncations (Uk11) or elimination of secondary structural amphiphilicity of Uk14 result in decreased efficiency. (Supplementary Table S1 and Supplementary Figure S1)

Summary

Introduction

Cytolytic peptides typically have both cationic and amphiphilic properties, resulting in the lysis of cells in a nonspecific manner. These cytolytic peptides induce cell lysis by associating with the plasma membrane via electrostatic interactions These interactions disrupt the membrane and form pores, leading to rapid necrotic cell death.[1] Conventional cancer chemotherapies develop drug resistance quickly, and novel therapeutics are in urgent need. Various new classes of promising cancer therapeutics have emerged recently, including cytolytic peptides[2] and oncolytic viruses.[3] For example, melittin, a major constituent of bee venom, raised interest as a potential anticancer reagent in recent years.[4,5,6]

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Conclusion