一种针对 HIV-1 RNA 基因组反式激活反应元件的肽核酸-氨基糖缀合物在人细胞中具有很高的生物利用度，并能强烈抑制 tat 介导的 HIV-1 转录的反式激活。
A peptide nucleic acid-aminosugar conjugate targeting transactivation response element of HIV-1 RNA genome shows a high bioavailability in human cells and strongly inhibits tat-mediated transactivation of HIV-1 transcription.
机构信息
Université de Grenoble I/CNRS, UMR 5063, Département de Pharmacochimie Moléculaire, ICMG FR 2607, 470 rue de la Chimie BP 53, F-38041 Grenoble, France.
出版信息
J Med Chem. 2012 Jul 12;55(13):6021-32. doi: 10.1021/jm300253q. Epub 2012 Jun 22.
Abstract
The 6-aminoglucosamine ring of the aminoglycoside antibiotic neomycin B (ring II) was conjugated to a 16-mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. For this purpose, we prepared the aminoglucosamine monomer 15 and attached it to the protected PNA prior to its cleavage from the solid support. We found that the resulting PNA-aminoglucosamine conjugate is stable under acidic conditions, efficiently taken up by the human cells and fairly distributed in both cytosol and nucleus without endosomal entrapment because cotreatment with endosome-disrupting agent had no effect on its cellular distribution. The conjugate displayed very high target specificity in vitro and strongly inhibited Tat mediated transactivation of HIV-1 LTR transcription in a cell culture system. The unique properties of this new class of PNA conjugate suggest it to be a potential candidate for therapeutic application.
摘要
新霉素 B（环 II）的 6-氨基葡萄糖胺环与针对 HIV-1 TAR RNA 的 16 聚体肽核酸（PNA）连接。为此，我们制备了氨基葡萄糖胺单体 15，并在从固相载体上切割之前将其连接到保护的 PNA 上。我们发现，所得的 PNA-氨基葡萄糖胺缀合物在酸性条件下稳定，可有效地被人类细胞摄取，并在细胞质和细胞核中均匀分布，而不会被内体捕获，因为用内体破坏剂共同处理对其细胞分布没有影响。该缀合物在体外显示出非常高的靶特异性，并在细胞培养系统中强烈抑制 Tat 介导的 HIV-1 LTR 转录的转激活。这种新型 PNA 缀合物的独特性质表明它可能成为治疗应用的潜在候选物。
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A peptide nucleic acid-aminosugar conjugate targeting transactivation response element of HIV-1 RNA genome shows a high bioavailability in human cells and strongly inhibits tat-mediated transactivation of HIV-1 transcription.一种针对 HIV-1 RNA 基因组反式激活反应元件的肽核酸-氨基糖缀合物在人细胞中具有很高的生物利用度，并能强烈抑制 tat 介导的 HIV-1 转录的反式激活。
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