title: Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy.
abstract: Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers.
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, 4072 Brisbane, Australia.
authors.forename: Lai Yue
authors.initials: LY
authors.lastname: Chan
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience, 4072 Brisbane, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, 4870 Cairns, Australia.
authors.forename: Norelle L
authors.initials: NL
authors.lastname: Daly
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D049033:Chorioallantoic Membrane / Q000737:chemistry; D047169:Cyclotides / Q000737:chemistry*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D000939:Epitopes / Q000737:chemistry*; D004912:Erythrocytes / Q000166:cytology; D006461:Hemolysis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008555:Melitten / Q000737:chemistry; D029775:Momordica / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011784:Quail; D015398:Signal Transduction / Q000187:drug effects; D014357:Trypsin / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D047169:Cyclotides; D000939:Epitopes; D010456:Peptides, Cyclic; C409923:trypsin inhibitor MCoTI-II; D008555:Melitten; D014357:Trypsin