Hetero-bivalent GLP-1/glibenclamide for targeting pancreatic β-cells.
Hetero-bivalent GLP-1/glibenclamide for targeting pancreatic β-cells.
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DOI：
10.1002/cbic.201300375
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发表时间：
2014-01-03
期刊：
影响因子：
3.2
通讯作者：
Lynch, Ronald M.
中科院分区：
文献类型：
--
作者：
Hart, Nathaniel J.;Chung, Woo Jin;Weber, Craig;Ananthakrishnan, Kameswari;Anderson, Miranda;Patek, Renata;Zhang, Zhanyu;Limesand, Sean W.;Vagner, Josef;Lynch, Ronald M.
Guanine nucleotide (G)-protein coupled receptor (GPCR) linked cell signaling cascades are initiated upon binding of a specific agonist ligand to its cell surface receptor. Linking multiple heterologous ligands that simultaneously bind and potentially cross-link different receptors on the cell surface is a unique approach to modulate cell responses. Moreover, if the target receptors are pre-selected, based on analysis of cell specific expression of a receptor combination, then the linked binding elements may provide enhanced specificity of targeting to the cell type of interest; i.e., only to cells that express the complementary receptors. Two receptors whose expression is relatively specific, as a combination, to the insulin secreting β-cell of the pancreas, are the sulfonylurea-1 (SUR1) and the glucagon-like peptide-1 (GLP-1) receptors. A heterobivalent ligand was assembled of the active fragment of GLP-1 ([Phe12, Arg36] 7-36 GLP-1) and glibenclamide,a small organic ligand to the SUR1. The synthetic construct was labelled with Cy5 or Europium chelated in DTPA to evaluate binding to β-cell lines using fluorescence microscopy or time-resolved saturation and competition binding assays, respectively. Once the ligand binds to β-cells, it is rapidly capped and presumably removed from the cell surface via endocytosis. The bivalent ligand had an affinity ~3 fold higher than monomeric Europium labelled GLP-1, likely due to cooperative binding to the complimentary receptors on the βTC3 cells. The high affinity binding was lost in the presence of either unlabelled monomer demonstrating that interaction with both receptors is required for the enhanced binding at low concentrations. Importantly, bivalent enhancement was accomplished in a cell system with physiological levels of expression of the complementary receptors, indicating that this approach may be applicable for β-cell targeting in vivo.
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影响因子：
7.3
作者：
Knudsen, LB;Nielsen, PF;Agerso, H
通讯作者：
Agerso, H
影响因子：
--
作者：
Quayum, Nayeem;Kutchma, Alecksandr;Jensen, Jan
通讯作者：
Jensen, Jan
影响因子：
4.7
作者：
Handl, Heather L.;Sankaranarayanan, Rajesh;Hruby, Victor J.
通讯作者：
Hruby, Victor J.
影响因子：
7.3
作者：
Brabez, Nabila;Lynch, Ronald M.;Hruby, Victor J.
通讯作者：
Hruby, Victor J.
影响因子：
2.9
作者：
Handl, HL;Vagner, J;Gillies, RJ
通讯作者：
Gillies, RJ