title: A new generation of potent complement inhibitors of the Compstatin family.
abstract: Compstatin family peptides are potent inhibitors of the complement system and promising drug candidates against diseases involving under-regulated complement activation. Compstatin is a 13-residue cyclized peptide that inhibits cleavage of complement protein C3, preventing downstream complement activation. We present three new compstatin variants, characterized by tryptophan replacement at positions 1 and/or 13. Peptide design was based on physicochemical reasoning and was inspired by earlier work, which identified tryptophan substitutions at positions 1 and 13 in peptides with predicted C3c binding abilities [Bellows M.L., Fung H.K., Taylor M.S., Floudas C.A., López de Victoria A., Morikis D. (2010) Biophys J; 98: 2337-2346]. The new variants preserve distinct polar and nonpolar surfaces of compstatin, but have altered local interaction capabilities with C3. All three peptides exhibited potent C3 binding by surface plasmon resonance and potent complement inhibition by enzyme-linked immunosorbent assay. We also present enzyme-linked immunosorbent assay data and detailed surface plasmon resonance kinetic data of three peptides from previous computational design.
authors.affiliation: Department of Bioengineering and Center for Bioengineering Research, University of California, Riverside, CA 92521, USA.
authors.forename: Aliana
authors.initials: A
authors.lastname: López de Victoria
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Gorham
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Bellows-Peterson
authors.forename: Jun
authors.initials: J
authors.lastname: Ling
authors.forename: David D
authors.initials: DD
authors.lastname: Lo
authors.forename: Christodoulos A
authors.initials: CA
authors.lastname: Floudas
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
mesh_terms: D000595:Amino Acid Sequence; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D003176:Complement C3; D010456:Peptides, Cyclic; C111828:compstatin