Engineering stablized vascular endothelial growth factor-A antagonists: synthesis, structural characterization and bioactivity of grafted analogues of cyclotides

Gunasekera, Sunithi, Foley, Fiona M., Clark, Richard J., Sando, Lillian, Fabri, Louis J., Craik, David J. and Daly, Norelle L. (2008) Engineering stablized vascular endothelial growth factor-A antagonists: synthesis, structural characterization and bioactivity of grafted analogues of cyclotides. Journal of Medicinal Chemistry, 51 24: 7697-7704. doi:10.1021/jm800704e


Author Gunasekera, Sunithi
Foley, Fiona M.
Clark, Richard J.
Sando, Lillian
Fabri, Louis J.
Craik, David J.
Daly, Norelle L.
Title Engineering stablized vascular endothelial growth factor-A antagonists: synthesis, structural characterization and bioactivity of grafted analogues of cyclotides
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2008-06-01
Year available 2008
Sub-type Article (original research)
DOI 10.1021/jm800704e
Open Access Status Not yet assessed
Volume 51
Issue 24
Start page 7697
End page 7704
Total pages 7
Editor Philip S. Portoghese
Place of publication United States
Publisher American Chemical Society
Language eng
Subject C1
8699 Other Manufacturing
030401 Biologically Active Molecules
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.
Keyword Chemistry, Medicinal
Pharmacology & Pharmacy
CHEMISTRY, MEDICINAL
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 16 Apr 2009, 19:38:01 EST by Jennifer Greder on behalf of Institute for Molecular Bioscience