The complement system, composed of more than 30 serum and cell surface components, is collaborating in the recognition and elimination of pathogens as a part of both the innate and acquired immune systems. The complement cascade causes protection against bacterial and viral invasion by promoting phagocytosis and inflammation. However, pathologically, an overactive complement can cause substantial damage to vasculitis, nephritis, arthritis, and erythrocytes (hemolysis) if not adequately controlled. Among them, complement component 5 (C5) is the fifth component of complement, which plays an important role in inflammatory and cell-killing processes. C5 shares the molecular structure consisting of two chains-α and β, linked by disulfide bonds, with C3 and C4. Moreover, C5 can be cleaved into C5a and C5b. C5a is an anaphylatoxin that has spasmogenic and chemotactic activity, meanwhile, C5b forms the first part of the complement membrane attack complex.

Zilucoplan (RA101495), a 15-amino acid macrocyclic peptide, is a potent human C5 inhibitor.

There are reports that Zilucoplan has little to no effect on rodent C5 cleavage, but does bind and inhibit human C5 cleavage. Mechanistically, the binding of Zilucoplan blocks the downstream assembly of the membrane attack complex (MAC; C5b-9) by inhibiting the cleavage of C5 by the C5 convertase into C5a and C5b. Besides, it binds to preformed C5b to sterically block interaction with C6. Through the two pathways, Zilucoplan inhibits the formation of membrane pores and subsequent cell death. In a humanized mouse model of immune-mediated necrotizing myopathy (IMNM), prophylactic administration of Zilucoplan prevents muscle strength loss. In addition, Zilucoplan reduces the C5b-9 deposits on myofibres and the number of regenerated myofibres. Overall, Zilucoplan has the potential for research on immune-mediated necrotizing myopathy and myasthenia gravis.

To sum up, Zilucoplan is a macrocyclic peptide inhibitor of human C5. It has the potential to research immune-mediated necrotizing myopathy and myasthenia gravis.


[1] Sarah Julien, et al. Biomedicines. 2022 Aug 20;10(8):2036.

[2] Declan M Gorman, et al. Amino Acids. 2021 Jan;53(1):143-147.