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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Inhibition of Cyclin-Dependent Kinase 1 by Purines and Pyrrolo(2,3-d)Pyrimidines Does Not Correlate with Antiviral Activity.
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Inhibition of Cyclin-Dependent Kinase 1 by Purines and Pyrrolo(2,3-d)Pyrimidines Does Not Correlate with Antiviral Activity.

机译：嘌呤和吡咯并（2,3-d）嘧啶对细胞周期蛋白依赖性激酶1的抑制作用与抗病毒活性无关。

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摘要

We have previously shown that a series of nonnucleoside pyrrolo[2,3-d]pyrimidines selectively inhibit the replication of herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV). These compounds act at the immediate-early or early stage of HCMV replication and have antiviral properties somewhat similar to those of roscovitine and olomoucine, specific inhibitors of cyclin-dependent kinases (cdks). In the present study we examine the hypothesis that pyrrolo[2,3-d]pyrimidines exert their antiviral effects by inhibition of cellular cdks. Much higher concentrations of a panel of pyrrolo[2,3-d]pyrimidine nucleoside analogs with antiviral activity were required to inhibit recombinant cdk1/cyclin B compared to the submicromolar concentrations required to inhibit HCMV and HSV-1 replication. 4,6-Diamino-5-cyano-7-(2-phenylethyl)pyrrolo[2,3-d]pyrimidine (compound 1369) was the best inhibitor of cdk1 and cyclin B, with a 50% inhibitory concentration (IC(50); 14 microM) similar to that of roscovitine; it was competitive with respect to ATP (K(i) = 14 microM). The potency of compound 1369 against cdk1 and cyclin B was similar to its cytotoxicity (IC(50)s, 32 to 100 microM) but not its antiviral efficacy (IC(50)s, 0.02 to 0.3 microM). Thus, our results indicated the null hypothesis. In contrast, roscovitine was only weakly active against HSV-1 (IC(50), 38 microM) and HCMV (IC(50), 40 microM). These values were similar to those derived by cytotoxicity and cell growth inhibition assays, thereby suggesting that roscovitine is not a selective antiviral. Therefore, we propose that inhibition of cdk1 and cyclin B is not responsible for selective antiviral activity and that pyrrolo[2,3-d]pyrimidines constitute novel pharmacophores which compete with ATP to inhibit cdk1 and cyclin B.
机译：我们以前已经表明，一系列非核苷吡咯并[2,3-d]嘧啶选择性抑制1型单纯疱疹病毒（HSV-1）和人巨细胞病毒（HCMV）的复制。这些化合物在HCMV复制的早期或早期起作用，并具有与roscovitine和olomoucine（细胞周期蛋白依赖性激酶（cdks）的特异性抑制剂）相似的抗病毒特性。在本研究中，我们检验了吡咯并[2,3-d]嘧啶通过抑制细胞cdks发挥其抗病毒作用的假设。与抑制HCMV和HSV-1复制所需的亚微摩尔浓度相比，抑制重组cdk1 / cyclin B所需的一组具有抗病毒活性的吡咯并[2,3-d]嘧啶核苷类似物的浓度要高得多。 4,6-二氨基-5-氰基-7-（2-苯乙基）吡咯并[2,3-d]嘧啶（化合物1369）是cdk1和细胞周期蛋白B的最佳抑制剂，抑制浓度为50％（IC（50 ）; 14 microM）类似于roscovitine;它相对于ATP具有竞争性（K（i）= 14 microM）。化合物1369对cdk1和细胞周期蛋白B的效力与其细胞毒性（IC（50）s，32至100 microM）相似，但与它的抗病毒效力（IC（50）s，0.02至0.3 microM）相似。因此，我们的结果表明了原假设。相反，roscovitine仅对HSV-1（IC（50），38 microM）和HCMV（IC（50），40 microM）具有弱活性。这些值与通过细胞毒性和细胞生长抑制试验得出的值相似，从而表明roscovitine不是选择性抗病毒药。因此，我们建议抑制cdk1和细胞周期蛋白B不负责选择性的抗病毒活性，并且吡咯并[2,3-d]嘧啶构成与ATP竞争抑制cdk1和细胞周期蛋白B的新型药效团。

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