Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells

Qifan Yang, Xianxiu Qiu, Xiaozhe Zhang, Yingting Yu, Na Li, Xing Wei, Guoqin Feng, Yan Li, Yanxiang Zhao, Renxiao Wang

Research output: Journal article publicationJournal articleAcademic researchpeer-review


Beclin 1 is an essential autophagy gene and a haploinsufficient tumor suppressor. Beclin 1 is the scaffolding member of the Class III phosphatidylinositol-3-kinase complex (PI3KC3) and recruits two positive regulators Atg14L and UVRAG through its coiled-coil domain to upregulate PI3KC3 activity. Our previous work has shown that hydrocarbon-stapled peptides targeted to the Beclin 1 coiled-coil domain reduced Beclin 1 homodimerization and promoted the Beclin 1-Atg14L/UVRAG interaction. These peptides also induced autophagy and enhanced the endolysosomal degradation of cell surface receptors like EGFR. Here, we present the optimization of these Beclin 1-targeting peptides by staple scanning and sequence permutation. Placing the hydrocarbon staple closer to the Beclin 1-peptide interface enhanced their binding affinity by ∼10- to 30-fold. Optimized peptides showed potent antiproliferative efficacy in cancer cells that overexpressed EGFR and HER2 by inducing necrotic cell death but not apoptosis. Our Beclin 1-targeting stapled peptides may serve as effective therapeutic candidates for EGFR- or HER2-driven cancer.

Original languageEnglish
Pages (from-to)13475-13486
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - 23 Sep 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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