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제111회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Covalent approaches to targeting cancer

2013년 3월 18일 17시 53분 08초
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목 14시 : 30분
[KCS-ACR joint Symposium] International Frontier Scientists Symposium on "Impact of Chemistry on Biology" hosted by KAST and co-organized by KCS & ACR
저자 및
Heather E. Beck, Bernadette V. Marquez1, Tololupe Aweda1, Claude Meares
Chemistry Department, University of California, Davis, California USA, United States
1Mallinckrodt Institute of Radiology, Washington University, St. Louis, Missouri USA, United States
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승인 4건

Vascular endothelial growth factor (VEGF) is a small, dimeric protein important for angiogenesis, the formation of new blood vessels. The elegant phage-display studies of Fairbrother and co-workers led to peptide ligands that blocked the receptor binding of VEGF, but with approximately micromolar dissociation constants, which are much weaker than the nano- to picomolar dissociation constants of acceptable drugs. While not a widely used design concept, a ligand that binds irreversibly to its target has several potential advantages over such weakly binding reversible ligands. For reversible binding, the concentration of free ligand must be larger than the dissociation constant in order for the target to be >50% occupied; for a covalent ligand, under ideal conditions the target could be titrated with equimolar ligand. Once tagged, the target is permanently inactivated, an outcome qualitatively different from reversible binding. To create a site on a weakly binding peptide ligand that would carry a covalent labeling reagent, we replaced a residue that does not change the peptide’s affinity for VEGF, but is located within reach of a lysine side chain on the protein. We will describe the interaction of reactively tagged peptides with VEGF, including recent studies in vivo in animal models, with particular focus on a nitroaryl fluoride reagent (see figure).

Fig.1. Marquez et al., Reactive peptide for inhibiting VEGF. Bioconjugate Chem., 2012, 23 (5), pp 1080?1089