Discovery of Zilucoplan: A Potent Macrocyclic Peptide Complement Component 5, C5, Inhibitor in Acetylcholine Receptor Antibody-positive Generalized Myasthenia Gravis
SESSION 11: PEPTIDE DESIGN AND FUNCTION
Wednesday, June 28, 2023, at 03:55 pm - 04:15 pm
Cyclic peptides are diverse molecules that are now a focus in drug discovery efforts. Their molecular size, between small molecules and biologics, provides attractive scaffolds to screen against some challenging targets, including protein-protein interactions and those considered to be "undruggable" proteins. With messenger ribonucleic acid (mRNA) display screening technology now able to produce trillions of peptide molecules for screening and quickly identify tight binders against targeting proteins, an exciting time of cyclic peptide drug discovery has come.
We have been working on cyclic peptide drug discovery since 2010, and have successfully identified two compounds derived from mRNA display that have entered clinical trials. One of them is a complement C5 inhibitor, zilucoplan, that has completed a phase III study with positive results in adult patients with AChR+ myasthenia gravis.
Here we present the discovery of zilucoplan, starting from hits identification via mRNA display screening against C5, followed by medicinal chemistry modifications to improve the potency, plasma stability and PK properties, leading to the clinical candidate.
Miss Ye is a highly skilled chemist in drug discovery. After obtained her master’s degree in chemistry from Eastern Illinois University, she joined ArQule in Boston, a leading combinatorial library synthesis company. She led a group of associate scientists on hit follow-up library synthesis in collaboration with Pfizer. Miss Ye then joined Pfizer, where she worked on kinase inhibitors and transitioned to the peptide nucleic acid space, when Pfizer transformed the kinase hub to a siRNA technology center.
In 2011, Miss Ye joined Ra Pharmaceuticals, a peptide drug discovery company, now part of UCB after a 2020 acquisition. At Ra/UCB, she worked in different stages of peptide drug discovery, from early hit to lead optimization and CRO management to late-stage SME (subject matter expert) supporting drug substance manufacture and control. She is part of the complement 5 inhibitor team that brought the mRNA display hits to zilucoplan, a cyclic peptide C5 inhibitor to treat generalized Myasthenia Gravis.