Y Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells
Y Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells
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DOI：
10.1021/acs.jmedchem.1c00870
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发表时间：
2021-09-10
影响因子：
7.3
通讯作者：
Wang, Renxiao
中科院分区：
文献类型：
--
作者：
Yang, Qifan;Qiu, Xianxiu;Wang, Renxiao
Beclin 1是一个重要的自噬基因，也是一个单倍不足的肿瘤抑制基因。Beclin 1是III类磷脂酰肌醇-3-激酶复合物（PI 3 KC 3）的支架成员，并通过其卷曲螺旋结构域招募两个正调节因子Atg 14 L和UVRAG以上调PI 3 KC 3活性。我们以前的工作已经表明，靶向Beclin 1卷曲螺旋结构域的烃钉合肽减少了Beclin 1的同源二聚化，并促进了Beclin 1-Atg 14 L/UVRAG相互作用。这些肽还诱导自噬并增强细胞表面受体如EGFR的内溶酶体降解。在这里，我们提出了优化这些Beclin 1靶向肽钉扫描和序列排列。将碳氢化合物钉靠近Beclin 1-肽界面放置，使它们的结合亲和力增强了10至30倍。优化的肽在过表达EGFR和HER 2的癌细胞中通过诱导坏死细胞死亡而非凋亡显示出有效的抗增殖功效。我们的Beclin 1靶向钉合肽可作为EGFR或HER 2驱动的癌症的有效治疗候选物。
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 similar to 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.