Homologous Peptide Foldamer Promotes FUS Aggregation and Triggers Cancer Cell Death,Journal of the American Chemical Society

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Homologous Peptide Foldamer Promotes FUS Aggregation and Triggers Cancer Cell Death
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-10-15 , DOI: 10.1021/jacs.4c03420
Man-Di Wang _{1,

2,

3} , Li Yi _{1,

3} , Yanying Li ₄ , Ruiwen Xu ₂ , Jiaojiao Hu _{5,

6} , Da-Yong Hou ₁ , Cong Liu _{5,

6} , Hao Wang _{1,

3}

Affiliation

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.

中文翻译：

同源肽折叠体促进 FUS 聚集并触发癌细胞死亡

融合在肉瘤（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 FUS 作为癌症治疗靶点的探索有限，主要是因为它的动态性质使其难以专门靶向。在这项研究中，我们探索了一种名为_β-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 RRM β 折叠的 β₄ 序列与 TAT（一种以其核靶向能力而闻名的肽）相结合，使_{β 4-TAT} 能够特异性结合 FUS 内的类似 β₄ 序列。值得注意的是，β_4-TAT 可有效诱导细胞内的 FUS 聚集，导致癌细胞死亡。我们的工作开发了一种基于肽折叠体的新型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。

更新日期：2024-10-15

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