Curated reading path
Follow zilucoplan discovery from early C5-inhibitory peptide hits through cyclic-peptide lead and candidate optimization.
3 published articles in recommended order
An mRNA display campaign for C5 inhibitors found a more potent linear peptide and a somewhat less potent but directly cyclizable peptide. Each supplied a different clue at the start of zilucoplan discovery.
Compound 1 was more potent but its linear structure exposed plasma-stability problems; Compound 2 was somewhat less potent but already macrocyclic. The team combined features from both to obtain Compound 32, then continued by optimizing the cyclization mode and degradation-prone sites.
Compound 38 already had strong C5-inhibitory activity, but the team still had to maintain sufficient in vivo exposure without compromising target binding. Lipidation and spacer design advanced the optimized molecule toward clinical development and ultimately once-daily subcutaneous zilucoplan.