Streeter D G, Witkowski J T, Khare G P, Sidwell R W, Bauer R J, Robins R K, Simon L N
Proc Natl Acad Sci U S A. 1973 Apr;70(4):1174-8. doi: 10.1073/pnas.70.4.1174.
The antiviral activity of the synthetic nucleoside, Virazole (1-beta-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 from Escherichia coli (K(m) = 1.8 x 10(-5) M) with a K(i) of 2.7 x 10(-7) M. Guanosine 5'-phosphate (GMP) was a competitive inhibitor of this enzyme with a K(i) of 7.7 x 10(-5) M. Virazole 5'-phosphate was similarly active against IMP dehydrogenase isolated from Ehrlich ascites tumor cells, with a K(i) of 2.5 x 10(-7) M. The K(m) for this enzyme was 1.8 x 10(-5) M, and the K(i) for GMP was 2.2 x 10(-4) M. 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.
合成核苷病毒唑（1-β-D-呋喃核糖基-1,2,4-三唑-3-甲酰胺）在Vero细胞培养物中对麻疹病毒的抗病毒活性，被黄苷、鸟苷显著逆转，被肌苷的逆转程度稍小。随后发现病毒唑5'-磷酸是从大肠杆菌中分离出的肌苷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（K(m)=1.8×10⁻⁵ M），K(i)为2.7×10⁻⁷ M。鸟苷5'-磷酸（GMP）是该酶的竞争性抑制剂，K(i)为7.7×10⁻⁵ M。病毒唑5'-磷酸对从艾氏腹水瘤细胞中分离出的IMP脱氢酶同样有活性，K(i)为2.5×10⁻⁷ M。该酶的K(m)为1.8×10⁻⁵ M，GMP的K(i)为2.2×10⁻⁴ M。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抑制了GMP生物合成中涉及IMP转化为黄苷5'-磷酸的步骤。这种抑制作用将因此导致重要病毒核酸合成的抑制。
