Discovery of Zilucoplan: A Complement C5 Inhibitor for Treatment of Anti-Acetylcholine Receptor (AChR) Antibody-Positive Generalized Myasthenia Gravis (gMG)

Complement component
5 (C5) is a protein in the complement
cascade
and a part of the innate immune system that has been clinically validated
as a therapeutic target for several immune-mediated diseases including
generalized myasthenia gravis (gMG). In this paper, we discuss the
early discovery of zilucoplan, a macrocyclic peptide drug, which was
identified via innovative extreme diversity mRNA display (Ma, Z.; Hartman, M. C. T. In Vitro Selection of Unnatural Cyclic Peptide Libraries
via mRNA Display. In Ribosome Display and
Related Technologies: Methods and Protocols; Douthwaite, J. A., Jackson, R. H., Eds.; Springer: New York, 2012; pp 367−390.) against C5 and
approved for the treatment of gMG. We highlight the key steps and
rationale behind the peptide medicinal chemistry optimization of the
initial screening hits, that led to improved potency, stability, and
pharmacokinetic properties.