2. Academic Validation
  3. Homologous Peptide Foldamer Promotes FUS Aggregation and Triggers Cancer Cell Death

Homologous Peptide Foldamer Promotes FUS Aggregation and Triggers Cancer Cell Death

  • J Am Chem Soc. 2024 Oct 23;146(42):28669-28676. 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
Affiliations

Affiliations

  • 1 CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), No. 11 Beiyitiao, Zhongguancun, 100190 Beijing, China.
  • 2 Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States.
  • 3 Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, No. 19A Yuquan Road, 100049 Beijing, China.
  • 4 Department of Medical Cell Biology Science for Life Laboratory, Uppsala University, Uppsala SE-75124, Sweden.
  • 5 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210 Shanghai, China.
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210 Shanghai, China.
PMID: 39403745 DOI: 10.1021/jacs.4c03420
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.

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