Heparan sulfate proteoglycan binding properties of adeno-associated virus retargeting mutants and consequences for their in vivo tropism
Heparan sulfate proteoglycan binding properties of adeno-associated virus retargeting mutants and consequences for their in vivo tropism
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DOI：
10.1128/jvi.00076-06
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发表时间：
2006-07-01
影响因子：
5.4
通讯作者：
Buening, Hildegard
中科院分区：
文献类型：
--
作者：
Perabo, Luca;Goldnau, Daniela;Buening, Hildegard
通过在病毒衣壳587号氨基酸位置插入配体肽，制备了腺相关病毒2型（AAV-2）靶向载体。在一些但不是所有的突变体中，这种方法会破坏AAV-2的主要受体硫酸肝素蛋白聚糖（HSPG）的结合。利用AAV-2展示库，我们研究了导致这种表型的分子机制，证明含有净负电荷的肽容易赋予HSPG非结合表型。有趣的是，体内研究表明，在全身应用AAV-2后，小鼠无法与HSPG结合与肝脏和脾脏脱靶有关，这表明有几种策略可以提高AAV-2重新靶向其他组织的效率。
Adeno-associated virus type 2 (AAV-2) targeting vectors have been generated by insertion of ligand peptides into the viral capsid at amino acid position 587. This procedure ablates binding of heparan sulfate proteoglycan (HSPG), AAV-2's primary receptor, in some but not all mutants. Using an AAV-2 display library, we investigated molecular mechanisms responsible for this phenotype, demonstrating that peptides containing a net negative charge are prone to confer an HSPG nonbinding phenotype. Interestingly, in vivo studies correlated the inability to bind to HSPG with liver and spleen detargeting in mice after systemic application, suggesting several strategies to improve efficiency of AAV-2 retargeting to alternative tissues.