Cell-specific targeting by heterobivalent ligands.
Cell-specific targeting by heterobivalent ligands.
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DOI：
10.1021/bc1004284
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发表时间：
2011-07-20
影响因子：
4.7
通讯作者：
Gillies, Robert J.
中科院分区：
文献类型：
--
作者：
Josan, Jatinder S.;Handl, Heather L.;Sankaranarayanan, Rajesh;Xu, Liping;Lynch, Ronald M.;Vagner, Josef;Mash, Eugene A.;Hruby, Victor J.;Gillies, Robert J.
目前的癌症疗法利用差异代谢或靶向在异常细胞中过表达的特定个体基因产物。本文所述的工作提出了一种替代方法-使用异多价配体特异性靶向细胞表面受体的组合（“受体组合方法”）。为了验证功能无关的受体可以以高亲合力和特异性非共价交联的概念，从黑皮质素肽配体（[Nle，DPhe]-α-MSH）和胆囊收缩素肽配体（CCK-8）的类似物构建了一系列异二价配体（htBVL）。分析了这些配体与表达人黑皮质素-4受体和胆囊收缩素-2受体的细胞的结合。MSH（7）和CCK（6）用不同刚性和长度的连接体连接，由天然和/或合成的结构单元构建。建模数据表明，需要20-50 μ m的接头长度来同时结合这两种不同的G蛋白偶联受体（GPCR）。这些配体表现出高达24倍的增强结合亲和力的细胞，表达两个（二价结合），与细胞相比，只有一个（单价结合）的同源受体。htBVL具有比单体CCK配体高50倍的亲和力，即，Ac-CCK（6）-NH2。用标记的异多价配体靶向这两种细胞类型的细胞表面表现出高亲合力和特异性，从而验证了受体组合方法。这种使用受体组合方法非共价交联异源受体和靶向单个细胞的能力为体内特异性细胞靶向治疗或成像开辟了新的可能性。
Current cancer therapies exploit either differential metabolism or targeting to specific individual gene products that are overexpressed in aberrant cells. The work described herein proposes an alternative approach—to specifically target combinations of cell-surface receptors using heteromultivalent ligands (“receptor combination approach”). As a proof-of-concept that functionally unrelated receptors can be noncovalently cross-linked with high avidity and specificity, a series of heterobivalent ligands (htBVLs) were constructed from analogues of the melanocortin peptide ligand ([Nle, DPhe]-α-MSH) and the cholecystokinin peptide ligand (CCK-8). Binding of these ligands to cells expressing the human Melanocortin-4 receptor and the Cholecystokinin-2 receptor was analyzed. The MSH(7) and CCK(6) were tethered with linkers of varying rigidity and length, constructed from natural and/or synthetic building blocks. Modeling data suggest that a linker length of 20–50 Å is needed to simultaneously bind these two different G-protein coupled receptors (GPCRs). These ligands exhibited up to 24-fold enhancement in binding affinity to cells that expressed both (bivalent binding), compared to cells with only one (monovalent binding) of the cognate receptors. The htBVLs had up to 50-fold higher affinity than that of a monomeric CCK ligand, i.e., Ac-CCK(6)-NH2. Cell-surface targeting of these two cell types with labeled heteromultivalent ligand demonstrated high avidity and specificity, thereby validating the receptor combination approach. This ability to noncovalently cross-link heterologous receptors and target individual cells using a receptor combination approach opens up new possibilities for specific cell targeting in vivo for therapy or imaging.
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影响因子：
5.7
作者：
Balagurunathan, Yoganand;Morse, David L.;Hostetter, Galen;Shanmugam, Vijayalakshmi;Stafford, Phillip;Shack, Sonsoles;Pearson, John;Trissal, Maria;Demeure, Michael J.;Von Hoff, Daniel D.;Hruby, Victor J.;GillieS, Robert J.;Han, Haiyong
通讯作者：
Han, Haiyong
DOI：
10.1073/pnas.93.24.13715
发表时间：
1996-11-26
影响因子：
11.1
作者：
Sharma, SD;Jiang, JW;Hruby, VJ
通讯作者：
Hruby, VJ
影响因子：
2.9
作者：
Ladokhin, AS;Selsted, ME;White, SH
通讯作者：
White, SH
影响因子：
4.7
作者：
Handl, Heather L.;Sankaranarayanan, Rajesh;Hruby, Victor J.
通讯作者：
Hruby, Victor J.
DOI：
10.1007/s002590050247
发表时间：
1998-05-01
期刊：
EUROPEAN JOURNAL OF NUCLEAR MEDICINE
影响因子：
--
作者：
Reubi, JC;Waser, B;Bugaj, JE
通讯作者：
Bugaj, JE