Synthesis and evaluation of bivalent NDP-α-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R)
Synthesis and evaluation of bivalent NDP-α-MSH(7) peptide ligands for binding to the human melanocortin receptor 4 (hMC4R)
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DOI：
10.1021/bc0603642
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发表时间：
2007-07-01
影响因子：
4.7
通讯作者：
Hruby, Victor J.
中科院分区：
文献类型：
--
作者：
Handl, Heather L.;Sankaranarayanan, Rajesh;Hruby, Victor J.
我们证明了多价配体作为癌症成像或治疗的靶向剂的潜在效用，通过确定同二价配体与其相应的受体的结合。该手稿详细描述了一系列二价配体的合成和评价，所述配体含有两个拷贝的截短的七肽形式的[Nle（4）-D-Phe（7）]-α-促黑素细胞激素（NDP-α-MSH），称为MSH（7）。这些与含有Pro-Gly重复序列的各种半刚性接头连接，在其末端具有或不具有柔性聚（乙二醇）（PEGO）部分。建模数据表明两个相邻的G蛋白偶联受体GPCR的配体结合位点之间的距离为20-50 A。观察到这些二价配体与其单价对应物相比以更高的亲和力结合。数据表明，这些配体可能能够交联相邻的受体。从这些配体推断的25 +/-10埃的最佳接头长度与通过建模估计的受体间距离良好相关。尽管用Pro-Gly重复构建的配体与用PEGO插入物构建的配体之间的最大结合亲和力没有差异，但含PEGO的配体在更大范围的接头长度上以高亲和力结合。
We demonstrate the potential utility of multivalent ligands as targeting agents for cancer imaging or therapy by determining the binding of homobivalent ligands to their corresponding receptors. This manuscript details the synthesis and evaluation of a series of bivalent ligands containing two copies of the truncated heptapeptide version of [Nle(4)-D-Phe(7)]-alpha-melanocyte stimulating hormone (NDP-alpha-MSH), referred to as MSH(7). These were connected with various semirigid linkers containing Pro-Gly repeats, with or without flexible poly(ethylene glycol) (PEGO) moieties at their termini. Modeling data suggest a distance of 20-50 A between the ligand binding sites of two adjacent G-protein coupled receptors, GPCRs. These bivalent ligands were observed to bind with higher affinity compared to their monovalent counterparts. Data suggest these ligands may be capable of cross-linking adjacent receptors. An optimal linker length of 25 +/- 10 angstrom, inferred from these ligands, correlated well with the inter-receptor distance estimated through modeling. Although there was no difference in maximal binding affinities between the ligands constructed with the Pro-Gly repeats versus those constructed with the PEGO inserts, the PEGO-containing ligands bound with high affinities over a greater range of linker lengths.