Precise Oligopeptides Block CCDC25 Interaction with DNA in Neutrophil Extracellular Traps Inhibiting Tumor Metastasis

Area of Science:

• Biochemistry
• Oncology
• Materials Science

Background:

• Neutrophil extracellular traps (NETs) promote tumor metastasis via interaction with cancer cell surface protein CCDC25.
• Positively charged polyamino acids have shown potential in inhibiting metastasis by neutralizing NET-DNA.

Purpose of the Study:

• To synthesize and evaluate cationic oligopeptides with defined arginine (R) and glycine (G) units for their efficacy in inhibiting tumor metastasis.
• To elucidate the structure-activity relationship of these oligopeptides in blocking CCDC25-NET-DNA interactions.

Main Methods:

• Precise synthesis of cationic oligopeptides (R5, R7, R9, R5G4, R3, R3G6).
• In vitro assays to assess binding affinity and cytotoxicity.
• Pull-down assays to evaluate inhibition of CCDC25 interaction with NET-DNA components (MPO, H3Cit).
• In vivo studies using triple-negative breast cancer (TNBC) mouse models to assess inhibition of cell migration and metastasis.

Main Results:

• Oligopeptides R5, R7, R9, and R5G4 exhibited superior binding affinity and lower cytotoxicity compared to R3 and R3G6.
• R5, R7, and R9 effectively inhibited the interaction between CCDC25 and NET-DNA by outcompeting MPO and H3Cit.
• In vivo studies demonstrated that R5, R7, and R9 significantly reduced TNBC metastasis to the liver and lungs, correlating with reduced NET accumulation.

Conclusions:

• Specific oligoarginines (R5, R7, R9) are effective in inhibiting triple-negative breast cancer metastasis.
• These oligopeptides function by disrupting the CCDC25-NET-DNA interaction, thereby preventing tumor cell dissemination.
• Oligoarginines represent a promising therapeutic strategy with low cytotoxicity for treating metastatic diseases and potentially reducing mortality rates.