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Wang MD, Yi L, Li Y, Xu R, Hu J, Hou DY, Liu C, Wang H
Journal of the American Chemical Society 146 (42) 28669-28676 [2024-10-23; online 2024-10-15]
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.
PubMed 39403745
DOI 10.1021/jacs.4c03420
Crossref 10.1021/jacs.4c03420