CORDYCEPIN ANALOGS OF 2',5'-OLIGOADENYLATE INHIBIT HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION VIA INHIBITION OF REVERSE-TRANSCRIPTASE
CORDYCEPIN ANALOGS OF 2',5'-OLIGOADENYLATE INHIBIT HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION VIA INHIBITION OF REVERSE-TRANSCRIPTASE
复制标题
DOI：
10.1021/bi00222a004
复制
发表时间：
1991-02-26
期刊：
影响因子：
2.9
通讯作者：
SCHRODER, HC
中科院分区：
文献类型：
--
作者：
MULLER, WEG;WEILER, BE;SCHRODER, HC
2 '，5'-寡腺苷酸（2-5A）的类似物，虫草素（3 '-脱氧腺苷）核心三聚体（Co 3）及其5'-单磷酸衍生物（pCo 3），显示出明显的体外抗人类免疫缺陷病毒1型（HIV-1）活性。 用1 μ M Co 3或pCo 3处理HIV-1感染的H9细胞导致几乎100%的病毒产生抑制。 将化合物包封在由T细胞受体分子CD 3特异性抗体靶向的脂质体中。 在Co_3或pCo_3中取代一个或两个虫草素单元会降低化合物的抗病毒活性。pCo 3不刺激2- 5A依赖的核糖核酸酶L活性，对细胞RNA和蛋白质的量没有影响。 在10 μ M的浓度下，细胞DNA聚合酶-α、β和γ对Co 3或pCo 3几乎不敏感。 相反，如果使用病毒RNA基因组和细胞tRNA（Lys.3）作为模板/引物系统;如果使用合成的poly（A），则这些化合物在10 μ M的浓度下将HIV-1逆转录酶（RT）的活性降低90%。（dT）10作为模板/引物，没有观察到显著的抑制。 斑点杂交、凝胶阻滞和交联试验表明Co 3或pCo 3干扰tRNA（Lys.3）与RT的结合位点。这些结果表明，在酶反应起始水平抑制RT是抑制HIV-1复制的一种新方法。
Analogues of 2',5'-oligoadenylates (2-5A), the cordycepin (3'-deoxyadenosine) core trimer (Co3) and its 5'-monophosphate derivative (pCo3), were shown to display pronounced anti-human immunodeficiency virus type 1 (HIV-1) activity in vitro. Treatment of HIV-1 infected H9 cells with 1-mu-M Co3 or pCo3 resulted in an almost 100% inhibition of virus production. The compounds were encapsulated in liposomes targeted by antibodies specific for the T-cell receptor molecule CD3. Substitution of one or two cordycepin units in Co3 or pCo3 decreased the antiviral activity of the compounds. pCo3 did not stimulate 2-5A-dependent ribonuclease L activity and displayed no effect on the amount of cellular RNA and protein. At a concentration of 10-mu-M the cellular DNA polymerases-alpha, beta, and gamma were almost insensitive toward Co3 or pCo3. In contrast, these compounds reduced the activity of HIV-1 reverse transcriptase (RT) by 90% at a concentration of 10-mu-M if the viral RNA genome and the cellular tRNA(Lys.3) was used as template/primer system; if the synthetic poly(A).(dT)10 was used as template/primer, no marked inhibition was observed. Dot-blot, gel-retardation, and cross-linking assays showed that Co3 or pCo3 interfere with the binding site of tRNA(Lys.3) to RT. These results indicate that inhibition of RT at the level of initiation of the enzymic reaction is a novel approach to inhibit HIV-1 replication.