Identification of Complin, a novel complement inhibitor that targets complement proteins factor B and C2.
Complement factor B (fB) is a key constituent of the alternative pathway (AP). Its central role in causing inflammation and tissue injury through activation of the AP urges the need for its therapeutic targeting. In the current study, we have screened phage-displayed random peptide libraries against fB and identified a novel cyclic hendecapeptide that inhibits activation of fB and the AP. Structure-activity studies revealed that: 1) the cysteine-constrained structure of the peptide is essential for its activity; 2) Ile5, Arg6, Leu7, and Tyr8 contribute significantly to its inhibitory activity; and 3) retro-inverso modification of the peptide results in loss of its activity. Binding studies performed using surface plasmon resonance suggested that the peptide has two binding sites on fB, which are located on the Ba and Bb fragments. Studies on the mechanism of inhibition revealed that the peptide does not block the interaction of fB with the activated form of C3, thereby suggesting that the peptide inhibits fB activation primarily by inhibiting its cleavage by factor D. The peptide showed a weak effect on preformed C3 and C5 convertases. Like inhibition of fB cleavage, the peptide also inhibited C2 cleavage by activated C1s and activation of the classical as well as lectin pathways. Based on its inhibitory activities, we named the peptide Complin.
Kadam
Archana P
AP
National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune, India.
Sahu
Arvind
A
D000595:Amino Acid Sequence; D003175:Complement C2 / Q000378:metabolism*; D011415:Complement Factor B / Q000378:metabolism*; D003169:Complement Inactivator Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003170:Complement Pathway, Alternative / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008969:Molecular Sequence Data; D019151:Peptide Library; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
D003175:Complement C2; D003169:Complement Inactivator Proteins; D019151:Peptide Library; D011415:Complement Factor B