FUS是一种多功能脱氧核糖核酸(DNA)/核糖核酸(RNA)结合蛋白,与多种癌症类型有关,包括肉瘤和白血病。尽管FUS与这些疾病有关,但对其作为癌症治疗靶点的探索有限,主要是因为其动态性使其难以具体靶向。
该文中,研究人员探索了一种名为β4-TAT的β-折叠肽,通过靶向其RNA识别基序(RRM)来影响FUS聚集。这种方法利用了肽自组装过程的非共价相互作用特性。
源自FUS RRMβ-片的β4序列与TAT(一种以核靶向能力而闻名的肽)结合,使β4-TAT能够特异性结合FUS内的类似β4序列。值得注意的是,β4-TAT有效诱导细胞内FUS聚集,导致癌症细胞死亡。
该工作开发了一种新的基于肽折叠体的策略来诱导蛋白质聚集,为靶向FUS相关癌症的创新治疗方法铺平了道路。
附:英文原文
Title: Homologous Peptide Foldamer Promotes FUS Aggregation and Triggers Cancer Cell Death
Author: Man-Di Wang, Li Yi, Yanying Li, Ruiwen Xu, Jiaojiao Hu, Da-Yong Hou, Cong Liu, Hao Wang
Issue&Volume: October 15, 2024
Abstract: Fused in sarcoma (FUS), a multifunctional deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)-binding protein, has been implicated in various cancer types, including sarcoma and leukemia. Despite its association with these diseases, there has been limited exploration of FUS as a cancer therapy target, primarily because its dynamic nature makes it difficult to target specifically. In this study, we explored a kind of β-sheet peptide foldamer, named β4-TAT, to influence FUS aggregation by targeting its RNA recognition motifs (RRM). This approach leverages the noncovalent interaction characteristics of peptide self-assembly processes. The β4 sequence, derived from the FUS RRM β-sheet, in combination with TAT, a peptide known for its nuclear targeting capability, enables β4-TAT to bind specifically to the analogous β4 sequence within FUS. Notably, β4-TAT effectively induces FUS aggregation within cells, leading to the death of cancer cells. Our work developed a novel peptide foldamer-based strategy for inducing protein aggregation, paving the way for innovative therapeutic approaches in targeting FUS-associated cancers.
DOI: 10.1021/jacs.4c03420
Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c03420
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官方网址:https://pubs.acs.org/journal/jacsat
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