title: Engineering stabilized vascular endothelial growth factor-A antagonists: synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides.
abstract: Cyclotides are plant derived mini-proteins with compact folded structures and exceptional stability. Their stability derives from a head-to-tail cyclized backbone coupled with a cystine knot arrangement of three-conserved disulfide bonds. Taking advantage of this stable framework we developed novel VEGF-A antagonists by grafting a peptide epitope involved in VEGF-A antagonism onto the stable cyclotide framework. Antagonists of this kind have potential therapeutic applications in diseases where angiogenesis is an important component of disease progression, including cancer and rheumatoid arthritis. A grafted analogue showed biological activity in an in vitro VEGF-A antagonism assay at low micromolar concentration and the in vitro stability of the target epitope was markedly increased using this approach. In general, the stabilization of bioactive peptide epitopes is a significant problem in medicinal chemistry and in the current study we have provided insight into one approach to stabilize these peptides in a biological environment.
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, Brisbane QLD 4072, Australia.
authors.forename: Sunithi
authors.initials: S
authors.lastname: Gunasekera
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Foley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Clark
authors.forename: Lillian
authors.initials: L
authors.lastname: Sando
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Fabri
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.forename: Norelle L
authors.initials: NL
authors.lastname: Daly
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D047169:Cyclotides / Q000737:chemistry*; D047168:Cystine Knot Motifs; D016503:Drug Delivery Systems; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry; D006461:Hemolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D008968:Molecular Conformation; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D047169:Cyclotides; D000939:Epitopes; D042461:Vascular Endothelial Growth Factor A