Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs.
Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs.
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通过用其他受体特异性肽基序替换其 RGD 基序，将腺病毒五邻体碱基靶向新受体。
作者：
Wickham Tj;M. E. Carrion;Imre Kovesdi
腺病毒外壳蛋白，五邻体碱基，含有肽基序RGD，其介导与整联蛋白细胞表面受体α v β 3和α v β 5的结合。然后这些整合素介导腺病毒内化。我们已经开发了五邻体基嵌合体，其通过用α v β 3-或α 4 β 1-特异性肽基序替换野生型RGD肽基序来识别组织特异性整联蛋白受体。在一个嵌合体中，原始haiRGDtfa基序被肽基序eiLDVpst替换，所述肽基序eiLDVpst介导嵌合体与整联蛋白α 4 β 1结合。这种整联蛋白在淋巴细胞和单核细胞上以高水平表达，但在上皮细胞或内皮细胞上不表达。在第二个嵌合体中，改变RGD基序侧翼的野生型序列以消除其与α v β 5的相互作用，同时保留其对α v β 3的特异性。整合素α v β 5主要在上皮细胞上表达，而整合素α v β 3通常在内皮细胞上表达。整合素α v β 3在某些转移性黑色素瘤和胶质母细胞瘤上也异常表达。缺失突变体缺乏的RGD序列不结合任何整联蛋白。这种掺入腺病毒病毒体的嵌合体可用于在腺病毒介导的基因递送中靶向特定组织。
The adenovirus coat protein, penton base, contains the peptide motif RGD which mediates binding to the integrin cell surface receptors alpha v beta 3 and alpha v beta 5. These integrins then mediate adenovirus internalization. We have developed penton base chimeras that recognize tissue-specific integrin receptors by replacing the wild-type RGD peptide motif with alpha v beta 3- or alpha 4 beta 1-specific peptide motifs. In one chimera the original haiRGDtfa motif was replaced with the peptide motif eiLDVpst which mediated chimera binding to the integrin alpha 4 beta 1. This integrin is expressed at high levels on lymphocytes and monocytes but is not expressed on epithelial or endothelial cells. In a second chimera the wild-type sequences flanking the RGD motif were altered to abrogate its interaction with alpha v beta 5 while retaining its specificity for alpha v beta 3. The integrin alpha v beta 5 is expressed primarily on epithelial cells whereas the integrin alpha v beta 3 is normally expressed on endothelial cells. The integrin alpha v beta 3 is also aberrantly expressed on certain metastatic melanomas and glioblastomas. A deletion mutant lacking the RGD sequence did not bind to any integrins. Such chimeras incorporated into adenovirus virions may be useful in targeting specific tissues in adenovirus-mediated gene delivery.