Engineering stabilized vascular endothelial growth factor-A antagonists: synthesis, structural characterization, and bioactivity of grafted analogues of cyclotides.
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.
Gunasekera
Sunithi
S
The University of Queensland, Institute for Molecular Bioscience, Brisbane QLD 4072, Australia.
Foley
Fiona M
FM
Clark
Richard J
RJ
Sando
Lillian
L
Fabri
Louis J
LJ
Craik
David J
DJ
Daly
Norelle L
NL
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*
D047169:Cyclotides; D000939:Epitopes; D042461:Vascular Endothelial Growth Factor A