Inhibition of HIV Replication by Cyclic and Hairpin PNAs Targeting the HIV-1 TAR RNA Loop.
Inhibition of HIV Replication by Cyclic and Hairpin PNAs Targeting the HIV-1 TAR RNA Loop.
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DOI：
10.1155/2012/591025
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发表时间：
2012
影响因子：
2.3
通讯作者：
Patino N
中科院分区：
文献类型：
--
作者：
Upert G;Di Giorgio A;Upadhyay A;Manvar D;Pandey N;Pandey VN;Patino N
人类免疫缺陷病毒-1（HIV-1）的复制和基因表达需要病毒蛋白达特与其反式激活应答元件（TAR）的特异性相互作用，以形成高度稳定的茎-凸起-环结构。先前，我们描述了基于三苯基鳞（TPP）阳离子的载体，其有效地将核苷酸类似物（PNA）递送到细胞的细胞质中。特别是，我们表明，TPP共轭物的线性16聚体PNA靶向顶端茎环区的TAR阻碍Tat介导的反式激活的HIV-1 LTR在体外，也在细胞培养系统。在这次交流中，我们将TPP与靶向HIV-1 TAR环区的环状和发夹PNA缀合，并在细胞培养系统中评估其抗病毒功效。我们发现，TPP-环状PNA只含有8个残基，显示出更高的抗病毒效力相比，发夹PNA的12或16个残基。我们进一步注意到，8-mer环状PNA的TPP-缀合物以及16-mer线性PNA显示出相似的抗病毒功效。然而，环状PNA显示出对其靶序列的高度特异性。该通信强调了小的约束环状PNA在线性和发夹结构上针对生物学相关RNA发夹的重要性。
Human immunodeficiency virus-1 (HIV-1) replication and gene expression entails specific interaction of the viral protein Tat with its transactivation responsive element (TAR), to form a highly stable stem-bulge-loop structure. Previously, we described triphenylphosphonium (TPP) cation-based vectors that efficiently deliver nucleotide analogs (PNAs) into the cytoplasm of cells. In particular, we showed that the TPP conjugate of a linear 16-mer PNA targeting the apical stem-loop region of TAR impedes Tat-mediated transactivation of the HIV-1 LTR in vitro and also in cell culture systems. In this communication, we conjugated TPP to cyclic and hairpin PNAs targeting the loop region of HIV-1 TAR and evaluated their antiviral efficacy in a cell culture system. We found that TPP-cyclic PNAs containing only 8 residues, showed higher antiviral potency compared to hairpin PNAs of 12 or 16 residues. We further noted that the TPP-conjugates of the 8-mer cyclic PNA as well as the 16-mer linear PNA displayed similar antiviral efficacy. However, cyclic PNAs were shown to be highly specific to their target sequences. This communication emphasizes on the importance of small constrained cyclic PNAs over both linear and hairpin structures for targeting biologically relevant RNA hairpins.