Elion G B
Am J Med. 1982 Jul 20;73(1A):7-13. doi: 10.1016/0002-9343(82)90055-9.
Acyclovir, an acrylic purine nucleoside analog, is a highly potent inhibitor of herpes simplex virus (HSV), types 1 and 2, and varicella zoster virus, and has extremely low toxicity for the normal host cells. This selectivity is due to the ability of these viruses to code for a viral thymidine kinase capable of phosphorylating acyclovir to a monophosphate; this capability is essentially absent in uninfected cells. The acyclovir monophosphate (acyclo-GMP) is subsequently converted to acyclovir triphosphate (acyclo-GTP) by cellular enzymes. Acyclo-GTP persists in HSV-infected cells for many hours after acyclovir is removed from the medium. The amounts of acyclo-GTP formed in HSV-infected cells are 40 to 100 times greater than in uninfected Vero cells. Acyclo-GTP acts as a more potent inhibitor of the viral DNA polymerases than of the cellular polymerases. The DNA polymerases of HSV-1 and HSV-2 also use acyclo-GTP as a substrate and incorporate acyclo-GMP into the DNA primer-template to a much greater extent than do the cellular enzymes. The viral DNA polymerase binds strongly to the acyclo-GMP-terminated template, and in thereby inactivated.
阿昔洛韦是一种丙烯酸嘌呤核苷类似物，是单纯疱疹病毒1型和2型以及水痘带状疱疹病毒的高效抑制剂，对正常宿主细胞的毒性极低。这种选择性是由于这些病毒能够编码一种病毒胸苷激酶，该激酶能够将阿昔洛韦磷酸化为单磷酸盐；未感染的细胞基本没有这种能力。阿昔洛韦单磷酸盐（阿昔洛韦-鸟苷一磷酸）随后通过细胞酶转化为阿昔洛韦三磷酸盐（阿昔洛韦-鸟苷三磷酸）。从培养基中去除阿昔洛韦后，阿昔洛韦-鸟苷三磷酸在单纯疱疹病毒感染的细胞中持续存在数小时。单纯疱疹病毒感染的细胞中形成的阿昔洛韦-鸟苷三磷酸的量比未感染的非洲绿猴肾细胞中的量高40至100倍。阿昔洛韦-鸟苷三磷酸对病毒DNA聚合酶的抑制作用比对细胞聚合酶的抑制作用更强。单纯疱疹病毒1型和2型的DNA聚合酶也将阿昔洛韦-鸟苷三磷酸用作底物，并比细胞酶更大量地将阿昔洛韦-鸟苷一磷酸掺入DNA引物-模板中。病毒DNA聚合酶与阿昔洛韦-鸟苷一磷酸终止的模板紧密结合，从而使其失活。
