ANTI-HERPES SIMPLEX VIRUS AND ANTI-HUMAN CELL-GROWTH ACTIVITY OF E-5-PROPENYL-2'-DEOXYURIDINE AND THE CONCEPT OF SELECTIVE PROTECTION IN ANTIVIRUS CHEMOTHERAPY
ANTI-HERPES SIMPLEX VIRUS AND ANTI-HUMAN CELL-GROWTH ACTIVITY OF E-5-PROPENYL-2'-DEOXYURIDINE AND THE CONCEPT OF SELECTIVE PROTECTION IN ANTIVIRUS CHEMOTHERAPY
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DOI：
10.1128/aac.18.6.957
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发表时间：
1980-01-01
影响因子：
4.9
通讯作者：
BERGSTROM, DE
中科院分区：
文献类型：
--
作者：
CHENG, YC;GRILL, S;BERGSTROM, DE
e -5-丙烯-2''-脱氧尿苷（e -5-丙烯- durd）抑制单纯疱疹病毒（HSV） 1型（HSV-1）和2型的生长。使病毒滴度降低2对数所需的药物浓度为5 μ m。HSV-1和23 .mu。M代表HSV-2。该制剂的抗hsv -1活性高于5-丙基durd，相当于E-5-（3,3,3-三氟丙基）- durd，而低于E-5-溴丙基durd。缺乏诱导病毒特异性胸苷激酶能力的HSV-1突变体（B2006）不能被e -5-丙烯- durd抑制。e -5-丙烯- durd与HSV-1、HSV-2、水痘带状疱疹病毒和人线粒体胸腺嘧啶激酶的结合常数分别为0.2、6.2、0.3和0.8 .mu。M,分别。胸腺嘧啶激酶催化的胸腺嘧啶磷酸化不能被浓度高于胸腺嘧啶10倍的e -5-丙烯- durd所抑制。当胸腺嘧啶和e -5-丙烯- durd同时以相同的浓度加入到病毒感染的细胞中时，对HSV-1的抗病毒活性没有逆转，对HSV-2的抗病毒活性只有部分逆转。e -5-丙烯- durd对人细胞的生长也有50%的抑制作用，抑制剂量为50 μ m。由于这种抑制可以很容易地被较低浓度的胸腺嘧啶逆转，因此提出了选择性保护的想法。这种方法可以避免具有类似e -5-丙烯- durd特性的抗病毒药物的细胞毒性作用，而不会牺牲抗病毒活性。
E-5-Propenyl-2''-deoxyuridine (E-5-propenyl-dUrd) inhibited the growth of herpes simplex virus (HSV) types 1 (HSV-1) and 2 in culture. The concentration of drug required to give a 2-log reduction in virus titer was 5 .mu.M for HSV-1 and 23 .mu.M for HSV-2. The anti-HSV-1 activity of this agent was more potent than 5-propyl-dUrd, equivalent to E-5-(3,3,3-trifluoropropenyl)-dUrd and less potent than E-5-bromovinyl-dUrd. The HSV-1 mutant (B2006) lacking the ability to induce virus-specific thymidine kinase could not be inhibited by E-5-propenyl-dUrd. The binding constants of E-5-propenyl-dUrd to HSV-1, HSV-2, varicella-zoster virus and human mitochondrial thymidine kinases were established to be 0.2, 6.2, 0.3 and 0.8 .mu.M, respectively. Thymidine phosphorylation catalyzed by human cytosol thymidine kinase could not be inhibited by E-5-propenyl-dUrd at a concentration 10-fold higher than the thymidine in the assay. When thymidine and E-5-propenyl-dUrd were added concomitantly at equal concentrations to virus-infected cells, the antiviral activity was not reversed in HSV-1 and only partially reversed in HSV-2. E-5-Propenyl-dUrd also inhibited the growth of human cells in culture with 50% inhibitory dose of 50 .mu.M. Since this inhibition could be readily reversed by a lower concentration of thymidine, the idea of selective protection is proposed. This approach could avoid the cytotoxic effect of an antiviral agent with properties similar to E-5-propenyl-dUrd without sacrificing antiviral activity.