腺相关病毒重靶向突变体的硫酸乙酰肝素蛋白聚糖结合特性及其对体内嗜性的影响。
Heparan sulfate proteoglycan binding properties of adeno-associated virus retargeting mutants and consequences for their in vivo tropism.
作者信息
Perabo Luca, Goldnau Daniela, White Kathryn, Endell Jan, Boucas Jorge, Humme Sibille, Work Lorraine M, Janicki Hanna, Hallek Michael, Baker Andrew H, Büning Hildegard
机构信息
Genzentrum, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, Munich, Germany.
出版信息
J Virol. 2006 Jul;80(14):7265-9. doi: 10.1128/JVI.00076-06.
Abstract
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.
摘要
通过将配体肽插入病毒衣壳的氨基酸位置587，已构建出2型腺相关病毒（AAV-2）靶向载体。此操作在部分但并非所有突变体中消除了硫酸乙酰肝素蛋白聚糖（HSPG）（AAV-2的主要受体）的结合。利用AAV-2展示文库，我们研究了导致该表型的分子机制，证明带有净负电荷的肽易于赋予HSPG非结合表型。有趣的是，体内研究表明，全身应用后，无法与HSPG结合与小鼠肝脏和脾脏脱靶相关，这提示了几种提高AAV-2重新靶向至其他组织效率的策略。
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2
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3
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4
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Circulation. 2004 Feb 3;109(4):513-9. doi: 10.1161/01.CIR.0000109697.68832.5D. Epub 2004 Jan 19.
5
AAV-based gene transfer.基于腺相关病毒的基因转移。
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6
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J Virol. 2002 May;76(9):4559-66. doi: 10.1128/jvi.76.9.4559-4566.2002.
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