title: New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics.
abstract: Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non-natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with α-modified non-natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Because of their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases.
authors.affiliation: Department of Bioengineering, University of California , Riverside, California 92521, United States.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Gorham
authors.forename: David L
authors.initials: DL
authors.lastname: Forest
authors.forename: George A
authors.initials: GA
authors.lastname: Khoury
authors.forename: James
authors.initials: J
authors.lastname: Smadbeck
authors.forename: Consuelo N
authors.initials: CN
authors.lastname: Beecher
authors.forename: Evangeline D
authors.initials: ED
authors.lastname: Healy
authors.forename: Phanourios
authors.initials: P
authors.lastname: Tamamis
authors.forename: Georgios
authors.initials: G
authors.lastname: Archontis
authors.forename: Cynthia K
authors.initials: CK
authors.lastname: Larive
authors.forename: Christodoulos A
authors.initials: CA
authors.lastname: Floudas
authors.forename: Monte J
authors.initials: MJ
authors.lastname: Radeke
authors.forename: Lincoln V
authors.initials: LV
authors.lastname: Johnson
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Morikis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D051056:Complement Inactivating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D055213:Retinal Pigment Epithelium / Q000187:drug effects; D012995:Solubility
chemical_list: D051056:Complement Inactivating Agents; D010456:Peptides, Cyclic; C111828:compstatin