@article{5d36b965d62243a788e91c72e18bad62,
title = "Optimization of Beclin 1-Targeting Stapled Peptides by Staple Scanning Leads to Enhanced Antiproliferative Potency in Cancer Cells",
abstract = "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.",
author = "Qifan Yang and Xianxiu Qiu and Xiaozhe Zhang and Yingting Yu and Na Li and Xing Wei and Guoqin Feng and Yan Li and Yanxiang Zhao and Renxiao Wang",
note = "Funding Information: The work was supported by grants from the Research Grants Council of Hong Kong (N-PolyU503/16, PolyU 151052/16M, PolyU 151015/17M, R5050-18, C4002-17G, and AoE/M-09/12), Shenzhen Basic Research Program of China (JCYJ20170818104619974 and JCYJ20180306173813203) and Hong Kong Polytechnic University to Y.Z.; Shenzhen Basic Research Program (JCYJ20180306173853283), National Natural Science Foundation of China (32000864), Guangdong Basic and Applied Basic Research Foundation (2019A1515110357, 2021A1515012054), Science and Technology Program of Zhanjiang (2020A01028) and Discipline construction project of Guangdong Medical University (4SG21003G) to X.Q.; Ministry of Science and Technology of China (2016YFA0502302), National Natural Science Foundation of China (81725022, 81430083, and 21661162003) to R.W. All authors have given approval to the final version of the manuscript. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2021 American Chemical Society",
year = "2021",
month = sep,
day = "23",
doi = "10.1021/acs.jmedchem.1c00870",
language = "English",
volume = "64",
pages = "13475--13486",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",
}