Engineering pro-angiogenic peptides using stable, disulfide-rich cyclic scaffolds.
Fragments from the extracellular matrix proteins laminin and osteopontin and a sequence from VEGF have potent proangiogenic activity despite their small size (< 10 residues). However, these linear peptides have limited potential as drug candidates for therapeutic angiogenesis because of their poor stability. In the present study, we show that the therapeutic potential of these peptides can be significantly improved by "grafting" them into cyclic peptide scaffolds. Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) and sunflower trypsin inhibitor-1 (SFTI-1), naturally occurring, plant-derived cyclic peptides of 34 and 14 residues, respectively, were used as scaffolds in this study. Using this approach, we have designed a peptide that, in contrast to the small peptide fragments, is stable in human serum and at nanomolar concentration induces angiogenesis in vivo. This is the first report of using these scaffolds to improve the activity and stability of angiogenic peptide sequences and is a promising approach for promoting angiogenesis for therapeutic uses.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Lai Y
LY
Chan
Sunithi
S
Gunasekera
Sonia T
ST
Henriques
Nathalie F
NF
Worth
Sarah-Jane
SJ
Le
Richard J
RJ
Clark
Julie H
JH
Campbell
David J
DJ
Craik
Norelle L
NL
Daly
D000595:Amino Acid Sequence; D042501:Angiogenic Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D047169:Cyclotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability; D051381:Rats
D042501:Angiogenic Proteins; D047169:Cyclotides; D004220:Disulfides; D010456:Peptides, Cyclic; C448501:SFTI-1 peptide, sunflower; C409923:trypsin inhibitor MCoTI-II