Inhibition of HIV-1 replication by anti-trans-activation responsive polyamide nucleotide analog
Inhibition of HIV-1 replication by anti-trans-activation responsive polyamide nucleotide analog
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DOI：
10.1016/s0166-3542(02)00024-4
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发表时间：
2002-10-01
影响因子：
7.6
通讯作者：
Pandey, VN
中科院分区：
文献类型：
--
作者：
Kaushik, N;Basu, A;Pandey, VN
人类免疫缺陷病毒-1（HIV-1）的有效复制和基因表达涉及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，所述TAR形成高度稳定的茎环结构。我们先前已经表明，靶向TAR的环和凸起区域的15聚体聚酰胺核苷酸类似物（PNA）在体外和细胞培养中阻断Tat介导的HIV-1 LTR的反式激活（Mayhood等人，Biochemistry 39（2000）11532）。在这次交流中，我们设计了四种不同长度的抗TAR PNA，使它们要么补充整个环和凸出区（PNA（TAR-16）和PNA（TAR-15）），要么在环中缺少少量序列（PNA（TAR-13））或在环和凸出区（PNA（TAR-12）），并在体外以及HIV-1感染的细胞培养物中检查了它们的功能功效。所有四种抗TAR PNA对TAR RNA都表现出很强的亲和力，而它们阻断体外逆转录的能力受到它们的长度的影响。与PNA（TAR-12）和PNA（TAR-13）形成鲜明对比的是，两种较长的PNA（TAR）能够有效地隔离TAR RNA上的靶位点，从而基本上抑制Tat介导的HIV-1 LTR的反式激活。此外，注意到所有四种抗TAR PNA对病毒产生的实质性抑制，其中PNA（TAR-16）表现出HIV-1产生的急剧减少近99%。这些结果表明PNA（TAR-16）作为潜在的抗HIV剂。(C)2002 Elsevier Science B. V.保留所有权利。
Efficient replication and gene expression of human immunodeficiency virus-1 (HIV-1) involves specific interaction of the viral protein Tat, with its trans-activation responsive element (TAR) which forms a highly stable stem-loop structure. We have earlier shown that a 15-mer polyamide nucleotide analog (PNA) targeted to the loop and bulge region of TAR blocks Tat-mediated transactivation of the HIV-1 LTR both in vitro and in cell culture (Mayhood et al., Biochemistry 39 (2000) 11532). In this communication, we have designed four anti-TAR PNAs of different length such that they either complement the entire loop and bulge region (PNA(TAR-16) and PNA(TAR-15)) or are short of few sequences in the loop (PNA(TAR-13)) or in both the loop and bulge (PNA(TAR-12)), and examined their functional efficacy in vitro as well as in HIV-1 infected cell cultures. All four anti-TAR PNAs showed strong affinity for TAR RNA, while their ability to block in vitro reverse transcription was influenced by their length. In marked contrast to PNA(TAR-12) and PNA(TAR-13), the two longer PNA(TARs) were able to efficiently sequester the targeted site on TAR RNA, thereby substantially inhibiting Tat-mediated transactivation of the HIV-1 LTR. Further, a substantial inhibition of virus production was noted with all the four anti-TAR PNA, with PNA(TAR-16) exhibiting a dramatic reduction of HIV-1 production by nearly 99%. These results point to PNA(TAR-16) as a potential anti-HIV agent. (C) 2002 Elsevier Science B.V. All rights reserved.