Identification of Complin, a novel complement inhibitor that targets complement proteins factor B and C2

Area of Science:

• Immunology
• Biochemistry

Background:

• Complement factor B (fB) is crucial for the alternative pathway (AP) of complement activation.
• AP activation leads to inflammation and tissue injury, highlighting the need for therapeutic targets.

Purpose of the Study:

• To identify and characterize novel inhibitors of complement factor B (fB).
• To explore the therapeutic potential of a newly discovered peptide targeting the alternative pathway.

Main Methods:

• Phage-displayed random peptide libraries were screened against fB.
• Structure-activity relationship studies were conducted on the identified peptide.
• Surface plasmon resonance was used for binding studies.
• Mechanism of inhibition was investigated through various complement assays.

Main Results:

• A novel cyclic hendecapeptide, named Complin, was identified that inhibits fB and AP activation.
• The cysteine-constrained structure and specific amino acid residues (Ile5, Arg6, Leu7, Tyr8) are essential for activity.
• Complin binds to both Ba and Bb fragments of fB.
• The peptide inhibits fB cleavage by factor D and also affects C2 cleavage, impacting classical and lectin pathways.

Conclusions:

• Complin is a potent inhibitor of complement factor B (fB) and the alternative pathway (AP).
• Its mechanism involves inhibiting fB cleavage by factor D, with broader effects on other complement pathways.
• Complin represents a promising therapeutic candidate for conditions driven by complement-mediated inflammation.