title: Structure-activity relationships for substrate-based inhibitors of human complement factor B.
abstract: Human complement is a cascading network of plasma proteins important in immune defense, cooperatively effecting recognition, opsonization, destruction, and removal of pathogens and infected/damaged cells. Overstimulated or unregulated complement activation can result in immunoinflammatory diseases. Key serine proteases in this cascade are difficult to study due to their multiprotein composition, short lifetimes, formation on membranes, or serum circulation as inactive zymogens. Factor B is inactive at pH 7, but a catalytically active serine protease under alkaline conditions, enabling structure-activity relationship studies for 63 substrate-based peptide inhibitors with 4-7 residues and a C-terminal aldehyde. A potent factor B inhibitor was hexpeptide Ac-RLTbaLAR-H (IC(50) 250 nM, pH 9.5), which at pH 7 also blocked formation of membrane attack complex via the "alternative pathway" of complement activation and inhibited human complement mediated lysis of rabbit erythrocytes. Inhibitors of factor B may be valuable probes and drug leads for complement mediated immunity and disease.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ruiz-Gómez
authors.forename: Junxian
authors.initials: J
authors.lastname: Lim
authors.forename: Maria A
authors.initials: MA
authors.lastname: Halili
authors.forename: Giang T
authors.initials: GT
authors.lastname: Le
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Madala
authors.forename: Giovanni
authors.initials: G
authors.lastname: Abbenante
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000187:drug effects*; D011415:Complement Factor B / Q000037:antagonists & inhibitors*; D003170:Complement Pathway, Alternative; D004912:Erythrocytes; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D011415:Complement Factor B