Elion G B, Furman P A, Fyfe J A, de Miranda P, Beauchamp L, Schaeffer H J
Proc Natl Acad Sci U S A. 1977 Dec;74(12):5716-20. doi: 10.1073/pnas.74.12.5716.
A guanine derivative with an acyclic side chain, 2-hydroxyethoxymethyl, at position 9 has potent antiviral activity [dose for 50% inhibition (ED(50)) = 0.1 muM] against herpes simplex virus type 1. This acyclic nucleoside analog, termed acycloguanosine, is converted to a monophosphate by a virus-specified pyrimidine deoxynucleoside (thymidine) kinase and is subsequently converted to acycloguanosine di- and triphosphates. In the uninfected host cell (Vero) these phosphorylations of acycloguanosine occur to a very limited extent. Acycloguanosine triphosphate inhibits herpes simplex virus DNA polymerase (DNA nucleotidyltransferase) 10-30 times more effectively than cellular (HeLa S3) DNA polymerase. These factors contribute to the drug's selectivity; inhibition of growth of the host cell requires a 3000-fold greater concentration of drug than does the inhibition of viral multiplication. There is, moreover, the strong possibility of chain termination of the viral DNA by incorporation of acycloguanosine. The identity of the kinase that phosphorylates acycloguanosine was determined after separation of the cellular and virus-specified thymidine kinase activities by affinity chromatography, by reversal studies with thymidine, and by the lack of monophosphate formation in a temperature-sensitive, thymidine kinase-deficient mutant of the KOS strain of herpes simplex virus type 1 (tsA1).
一种在9位带有无环侧链2 - 羟基乙氧基甲基的鸟嘌呤衍生物，对1型单纯疱疹病毒具有强大的抗病毒活性[50%抑制剂量（ED(50)）= 0.1 μM]。这种无环核苷类似物，称为阿昔洛韦，通过病毒特异性嘧啶脱氧核苷（胸苷）激酶转化为单磷酸，随后再转化为阿昔洛韦二磷酸和三磷酸。在未感染的宿主细胞（Vero细胞）中，阿昔洛韦的这些磷酸化反应程度非常有限。阿昔洛韦三磷酸对单纯疱疹病毒DNA聚合酶（DNA核苷酸转移酶）的抑制作用比对细胞（HeLa S3）DNA聚合酶的抑制作用有效10 - 30倍。这些因素促成了该药物的选择性；抑制宿主细胞生长所需的药物浓度比抑制病毒增殖所需的浓度高3000倍。此外，通过掺入阿昔洛韦使病毒DNA链终止的可能性很大。在通过亲和色谱分离细胞和病毒特异性胸苷激酶活性后，通过与胸苷的逆转研究，以及在1型单纯疱疹病毒KOS株的温度敏感、胸苷激酶缺陷突变体（tsA1）中缺乏单磷酸形成，确定了使阿昔洛韦磷酸化的激酶的特性。
