PEGylated dendritic unimolecular micelles as versatile carriers for ligands of G protein-coupled receptors.
PEGylated dendritic unimolecular micelles as versatile carriers for ligands of G protein-coupled receptors.
复制标题
DOI：
10.1021/bc9001689
复制
发表时间：
2009-10-21
影响因子：
4.7
通讯作者：
Jacobson KA
中科院分区：
文献类型：
--
作者：
Kim Y;Hechler B;Gao ZG;Gachet C;Jacobson KA
尽管其在纳米医学中的广泛应用，但由于潜在的空间复杂性，聚（乙二醇）（PEG）很少用于G蛋白偶联受体（GPCR）配体的共价修饰。为了研究PEG链对与普通大分子载体结合的GPCR配体的生物活性的影响，我们制备了一系列用Alexa Fluor 488衍生的G3聚酰胺胺（PAMAM）树枝状聚合物，不同数量的PEG 550/PEG 750/PEG 2000，和衍生自A2 A腺苷受体（AR）激动剂CGS 21680（2-[4-（2-羧基乙基）苯乙基氨基]-5′-N-乙基甲酰胺腺苷）的核苷部分。这些树枝状聚合物的共轭物进行了纯化，通过尺寸排阻色谱法和1H NMR和MALDI MS的特点。在放射性配体结合试验中，一些PAMAM-PEG共轭物表现出增强的亚型选择性在人A2 A AR相比，单体配体的亲和力。在A2 A AR介导的腺苷酸环化酶活化和ADP诱导的血小板聚集抑制中测量功能效力。有趣的是，带有11个PEG 750链的树枝状聚合物缀合物10 c（理论上不存在）。32个氨基末端基团）和14个核苷部分的10 d在A2 A AR介导的环AMP形成刺激中的效力是具有4个PEG 2000链和21个核苷的10 d的5倍，尽管这两种化合物的结合亲和力相似。因此，相对小的（≤10 nm）经水溶性修饰的多价配体10 c保持了高效力，并显示出相对于单体核苷增加的A2 A AR结合选择性。较长的PEG链降低了A2 A AR处的亲和力。目前的研究表明，在靶向配体-受体相互作用的载体设计中使用短PEG链的可行性。
Despite its widespread application in nanomedicine, poly(ethylene glycol) (PEG) is seldom used for covalent modification of ligands for G protein-coupled receptors (GPCRs) due to potential steric complications. In order to study the influence of PEG chains on the biological activity of GPCR ligands bound to a common macromolecular carrier, we prepared a series of G3 polyamidoamine (PAMAM) dendrimers derivatized with Alexa Fluor 488, varying numbers of PEG550/PEG750/PEG2000, and nucleoside moieties derived from the A2A adenosine receptor (AR) agonist CGS21680 (2-[4-(2-carboxylethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine). These dendrimer conjugates were purified by size exclusion chromatography and characterized by 1H NMR and MALDI MS. In radioligand binding assays, some PAMAM-PEG conjugates showed enhanced subtype-selectivity at the human A2A AR compared to monomeric ligands of comparable affinity. The functional potency was measured in the A2A AR-mediated activation of adenylate cyclase and inhibition of ADP-induced platelet aggregation. Interestingly, the dendrimer conjugate 10c bearing 11 PEG750 chains (out of theo. 32 amino end groups) and 14 nucleoside moieties was 5-fold more potent in A2A AR–mediated stimulation of cyclic AMP formation than 10d with four PEG2000 chains and 21 nucleosides, although the binding affinities of these two compounds were similar. Thus, a relatively small (≤10 nm) multivalent ligand 10c modified for water solubility maintained high potency and displayed increased A2A AR binding selectivity over the monomeric nucleosides. Longer PEG chains reduced affinity at the A2A AR. The current study demonstrates the feasiblity of using short PEG chains in the design of carriers that target ligand-receptor interactions.
登录
查看更多内容
影响因子：
14
作者：
Huang, Rongqin;Ke, Weilun;Pei, Yuanying
通讯作者：
Pei, Yuanying
影响因子：
4.7
作者：
Kim, Yoonkyung;Hechler, Beatrice;Jacobson, Kenneth A.
通讯作者：
Jacobson, Kenneth A.
DOI：
10.1126/science.1164772
发表时间：
2008-11-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jaakola VP;Griffith MT;Hanson MA;Cherezov V;Chien EY;Lane JR;Ijzerman AP;Stevens RC
通讯作者：
Stevens RC
影响因子：
3.5
作者：
Kim, Yoonkyung;Klutz, Athena M.;Hechler, Beatrice;Gao, Zhan-Guo;Gachet, Christian;Jacobson, Kenneth A.
通讯作者：
Jacobson, Kenneth A.
影响因子：
5.8
作者：
Gao, ZG;Mamedova, LK;Jacobson, KA
通讯作者：
Jacobson, KA