Homologous Peptide Foldamer Promotes FUS Aggregation and Triggers Cancer Cell Death

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Fused in sarcoma (FUS) is a DNA/RNA-binding protein linked to various cancers like sarcoma and leukemia.
• Targeting FUS is challenging due to its dynamic nature, limiting therapeutic development.
• Protein aggregation is a potential mechanism for targeting disease-associated proteins.

Purpose of the Study:

• To develop a novel peptide foldamer strategy to target and induce aggregation of the FUS protein.
• To investigate the efficacy of β4-TAT in targeting FUS RNA recognition motifs (RRMs).
• To explore the potential of FUS protein aggregation as a therapeutic approach for FUS-associated cancers.

Main Methods:

• Design and synthesis of a β-sheet peptide foldamer, β4-TAT, incorporating a FUS RRM-derived sequence and a nuclear-targeting peptide (TAT).
• Utilizing noncovalent interactions and peptide self-assembly principles to target FUS.
• Assessing the ability of β4-TAT to induce FUS aggregation within cancer cells.

Main Results:

• β4-TAT specifically binds to the analogous β4 sequence within FUS RRMs.
• The peptide effectively induces FUS protein aggregation in cellular models.
• Induced FUS aggregation led to the death of cancer cells.

Conclusions:

• A novel peptide foldamer-based strategy was successfully developed to induce protein aggregation.
• β4-TAT demonstrates potential as a therapeutic agent for targeting FUS-associated cancers.
• This approach opens new avenues for developing innovative cancer therapies by targeting protein aggregation.