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...
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Published in | Journal of medicinal chemistry Vol. 51; no. 24; pp. 7697 - 7704 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Columbus, OH
American Chemical Society
25.12.2008
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ark:/67375/TPS-SQ4QRPRV-Z Grafted peptide purity quantified by RP-HPLC; RP-HPLC traces of cpr1, cpr3, cpr5 and cpr6; mass spectra data for cpr1, cpr3, cpr5, and cpr6. This material is available free of charge via the Internet at http://pubs.acs.org. istex:2D81C31BDBAAFE68D0C46B3756E7D6D876CCFCF0 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm800704e |