Homologous Peptide\nFoldamer Promotes FUS Aggregation\nand Triggers Cancer Cell Death

Fused in sarcoma (FUS), a multifunctional deoxyribonucleic\nacid\n(DNA)/ribonucleic acid (RNA)-binding protein, has been implicated\nin various cancer types, including sarcoma and leukemia. Despite its\nassociation with these diseases, there has been limited exploration\nof FUS as a cancer therapy target, primarily because its dynamic nature\nmakes it difficult to target specifically. In this study, we explored\na kind of β-sheet peptide foldamer, named β<sub>4</sub>-TAT, to influence FUS aggregation by targeting its RNA recognition\nmotifs (RRM). This approach leverages the noncovalent interaction\ncharacteristics of peptide self-assembly processes. The β<sub>4</sub> sequence, derived from the FUS RRM β-sheet, in combination\nwith TAT, a peptide known for its nuclear targeting capability, enables\nβ<sub>4</sub>-TAT to bind specifically to the analogous β<sub>4</sub> sequence within FUS. Notably, β<sub>4</sub>-TAT effectively\ninduces FUS aggregation within cells, leading to the death of cancer\ncells. Our work developed a novel peptide foldamer-based strategy\nfor inducing protein aggregation, paving the way for innovative therapeutic\napproaches in targeting FUS-associated cancers.