Ayisi N K, De Clercq E, Wall R A, Hughes H, Sacks S L
Antimicrob Agents Chemother. 1984 Nov;26(5):762-5. doi: 10.1128/AAC.26.5.762.
(E)-5-(2-Bromovinyl)-2'-deoxyuridine is a potent antiherpes compound with far better activity against herpes simplex virus type 1 than type 2. To understand the role of drug metabolism in this differential antiviral activity, we examined the metabolic fate of this drug in virus-infected and mock-infected Vero cells by high-pressure liquid chromatography. After 8 h of incubation in which cells were exposed to 10 micrograms of the drug per ml, 63 pmol/10(6) cells of the parent compound was detected in acid-soluble extracts of mock-infected cells. Herpes simplex virus-infected cells, however, incorporated or metabolized, or both, up to 11,310 pmol/10(6) cells. Type 1-infected cells metabolized the drug to the triphosphate where as many as 5,565 pmol/10(6) cells were detected. In contrast, three strains of type 2-infected cells metabolized the drug to the monophosphorylated nucleotide and no further. The amount of drug getting into the cells was virus strain and inoculum dependent. These studies indicate that poor substrate acceptance of (E)-5-(2-bromovinyl)-2'-deoxyuridine monophosphate by herpes simplex virus type 2-specified thymidylate kinase is an important factor in situ in infected cells, preventing anabolism of the parent compound to its active triphosphorylated form. This may account for its type specificity.
（E）-5-（2-溴乙烯基）-2'-脱氧尿苷是一种强效抗疱疹化合物，对1型单纯疱疹病毒的活性远高于2型。为了解药物代谢在这种差异抗病毒活性中的作用，我们通过高压液相色谱法研究了该药物在病毒感染和模拟感染的Vero细胞中的代谢命运。在将细胞暴露于每毫升10微克药物的孵育8小时后，在模拟感染细胞的酸溶性提取物中检测到63皮摩尔/10⁶个细胞的母体化合物。然而，单纯疱疹病毒感染的细胞摄取或代谢了该药物，或者两者兼而有之，多达11310皮摩尔/10⁶个细胞。1型感染的细胞将该药物代谢为三磷酸形式，检测到多达5565皮摩尔/10⁶个细胞。相比之下，三株2型感染的细胞将该药物代谢为单磷酸化核苷酸，不再进一步代谢。进入细胞的药物量取决于病毒株和接种物。这些研究表明，2型单纯疱疹病毒特异性胸苷酸激酶对（E）-5-（2-溴乙烯基）-2'-脱氧尿苷单磷酸的底物接受性较差是感染细胞原位的一个重要因素，阻止母体化合物合成其活性三磷酸化形式。这可能解释了它的类型特异性。
