posted on 2021-09-10, 20:49authored byQifan Yang, Xianxiu Qiu, Xiaozhe Zhang, Yingting Yu, Na Li, Xing Wei, Guoqin Feng, Yan Li, Yanxiang Zhao, Renxiao Wang
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.