Structure-Function Correlation of Chloroquine and Analogues as Transgene Expression Enhancers in Nonviral Gene Delivery

详细信息    查看全文

• 作者：Jianjun Cheng ; Ryan Zeidan ; Swaroop Mishra ; Aijie Liu ; Suzie H. Pun ; Rajan P. Kulkarni ; Gregory S. Jensen ; Nathalie C. Bellocq ; Mark E. Davis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 2, 2006
• 年：2006
• 卷：49
• 期：22
• 页码：6522 - 6531
• 全文大小：492K
• 年卷期：v.49,no.22(November 2, 2006)
• ISSN：1520-4804

文摘

To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral genedelivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in thearomatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQis essential to provide increased gene expression. Further, the enhancements are more dramatically affectedby changes to the aromatic ring and are positively correlated to the strength of intercalation between DNAand the CQ analogues. Quinacrine (QC), a CQ analogue with a fused acridinyl structure that can stronglyintercalate DNA, enhances transfection similarly to CQ at a concentration 10 times lower, while N⁴-(4-pyridinyl)-N¹,N¹-diethyl-1,4-pentanediamine (CP), a CQ analogue that has a weakly intercalating pyridinylring, shows no effect on gene expression. Subtle change on the 7-substituent of the chloroquine aromaticstructure can also greatly affect the ability of the CQ analogues to enhance transgene expression. Transfectionin the presence of N⁴-(7-trifluoromethyl-4-quinolinyl)-N¹,N¹-diethyl-1,4-pentanediamin e (CQ7a) showsexpression efficiency 10 times higher than in the presence of CQ at same concentration, while transfectionin the presence of N⁴-(4-quinolinyl)-N¹,N¹-diethyl-1,4-pentanediamine (CQ7b) does not reveal any enhancingeffects on expression. Through a number of comparative studies with CQ and its analogues, we concludethat there are at least three mechanistic features of CQ that lead to the enhancement in gene expression: (i)pH buffering in endocytic vesicles, (ii) displacement of polycations from the nucleic acids in polyplexes,and (iii) alteration of the biophysical properties of the released nucleic acid.