Discovery of Cyclic Peptide Inhibitors Targeted on TNFα-TNFR1 from Computational Design and Bioactivity Verification

Area of Science:

• Biochemistry
• Immunology
• Drug Discovery

Background:

• Tumor necrosis factor receptor 1 (TNFR1) activation by tumor necrosis factor alpha (TNFα) exacerbates rheumatoid arthritis (RA) immune responses.
• Existing RA treatments have limitations, necessitating novel therapeutic strategies.
• Targeting the TNFα-TNFR1 interaction offers a promising avenue for developing new RA drugs.

Purpose of the Study:

• To elucidate the interaction mechanism between TNFα and TNFR1.
• To design and develop novel cyclic peptides targeting the TNFα-TNFR1 interaction for potential RA treatment.
• To optimize and validate the efficacy of designed peptides.

Main Methods:

• Detailed analysis of the TNFα-TNFR1 interaction mechanism.
• Design of linear peptides followed by head-to-tail cyclization using proline-glycine (GP) or cysteine-cysteine (CC) strategies.
• In vitro activity, toxicity, and binding affinity assays (ELISA) for peptide evaluation and optimization.

Main Results:

• Two cyclic peptides, R1_CC4 and α_CC8, demonstrated strong binding free energies with TNFR1.
• The α_CC8 peptide showed optimal biological activity and was selected for further optimization.
• The L16R mutant of α_CC8 exhibited validated binding affinity to TNFR1.

Conclusions:

• Novel cyclic peptides targeting the TNFα-TNFR1 interaction were successfully designed.
• The developed cyclic peptides possess potential anti-inflammatory properties.
• This study presents a promising new therapeutic option for rheumatoid arthritis treatment.