MECHANISM OF ACTION OF 1-BETA-D-RIBOFURANOSYL-1,2,4-TRIAZOLE-3-CARBOXAMIDE (VIRAZOLE) - NEW BROAD-SPECTRUM ANTIVIRAL AGENT
MECHANISM OF ACTION OF 1-BETA-D-RIBOFURANOSYL-1,2,4-TRIAZOLE-3-CARBOXAMIDE (VIRAZOLE) - NEW BROAD-SPECTRUM ANTIVIRAL AGENT
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DOI：
10.1073/pnas.70.4.1174
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发表时间：
1973-01-01
影响因子：
11.1
通讯作者：
SIMON, LN
中科院分区：
文献类型：
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作者：
STREETER, DG;WITKOWSKI, JT;SIMON, LN
在Vero细胞培养物中，合成核苷病毒唑（1-β- d -核糖呋喃基-1,2,4-三唑-3-羧酰胺）对麻疹病毒的抗病毒活性被黄嘌呤、鸟苷和肌苷略微逆转。随后发现，Virazole 5 ' -phosphate是一种从大肠杆菌（Km= 1.8 × 10-5M）中分离出来的肌苷5 ' -磷酸脱氢酶（IMP:NAD+氧化还原酶，EC 1.2.1.14）的有效竞争性抑制剂，其aki为2.7 × 10-7M。鸟苷5′-磷酸（GMP）是该酶的竞争性抑制剂，其aki7 × 10-5M。病毒唑5′-磷酸对从埃利希腹水肿瘤细胞分离的IMP脱氢酶具有相似的活性，其akik为2.5 × 10-7M。该酶的分子量为1.8 × 10-5M，分子量为2.2 × 10-4M。这些结果表明，病毒唑的抗病毒活性可能是由于在感染细胞中将IMP转化为5′-磷酸黄嘌呤的过程中抑制了GMP的生物合成。这种抑制会导致抑制重要病毒核酸的合成。
The antiviral activity of the synthetic nucleoside, Virazole (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), against measles virus in Vero cell cultures was substantially reversed by xanthosine, guanosine, and to a slightly lesser extent by inosine. Virazole 5′-phosphate was subsequently found to be a potent competitive inhibitor of inosine 5′-phosphate dehydrogenase (IMP:NAD+oxidoreductase, EC 1.2.1.14) isolated fromEscherichia coli(Km= 1.8 × 10-5M) with aKiof 2.7 × 10-7M. Guanosine 5′-phosphate (GMP) was a competitive inhibitor of this enzyme with aKiof 7.7 × 10-5M. Virazole 5′-phosphate was similarly active against IMP dehydrogenase isolated from Ehrlich ascites tumor cells, with aKiof 2.5 × 10-7M. TheKmfor this enzyme was 1.8 × 10-5M, and theKifor GMP was 2.2 × 10-4M. These results suggest that the antiviral activity of Virazole might be due to the inhibition of GMP biosynthesis in the infected cell at the step involving the conversion of IMP to xanthosine 5′-phosphate. This inhibition would consequently result in inhibition of the synthesis of vital viral nucleic acid.