S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE AS A TARGET FOR ANTIVIRAL CHEMOTHERAPY
S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE AS A TARGET FOR ANTIVIRAL CHEMOTHERAPY
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DOI：
10.1021/jm00109a001
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发表时间：
1991-05-01
影响因子：
7.3
通讯作者：
BORCHARDT, RT
中科院分区：
文献类型：
--
作者：
WOLFE, MS;BORCHARDT, RT
就在几十年前，人们还普遍认为寻找抗病毒药物是徒劳的。大多数病毒学家认为，病毒复制与细胞过程密切相关，对于这些病原体来说，“神奇子弹”不仅仅是幻想。自那以后，随着临床上有用的抗病毒药物的出现，这一教条被传递了下来，但这些药物的成功又承载了另一个坚定的信条：抗病毒药物应该选择性地与病毒大分子相互作用(即这些药物不应该干扰正常的细胞代谢过程)。1这一假设看起来既实用又合乎逻辑，因为给定毒副作用的原因通常可以追溯到某些基本细胞功能的紊乱。目前临床使用的核苷类抗病毒药物的一个共同机制是将它们代谢成相应的三磷酸，然后选择性地抑制病毒核酸聚合酶。例如，齐多夫定(3‘-齐多夫定，AZT，Retrovir)被细胞酶转化为它的5’-三磷酸，在治疗剂量下，这种代谢物选择性地灭活人类免疫缺陷病毒(HIV)的逆转录酶，而细胞聚合酶相对不受影响。2‘3阿昔洛韦的三磷酸代谢产物(9-[(2-羟乙氧基)甲基]鸟嘌呤，Zovirax)选择性地抑制单纯疱疹病毒I型(HSV I)的DNA聚合酶。事实上，这种鸟苷类似物对病毒编码的酶具有双重选择性，因为药物需要疱疹病毒胸苷激酶才能有效地转化为活性代谢物。4 56‘7
I. Introduction It was only a few decades ago that the search for antiviral agents was widely thought to be an exercise in futility. Most virologists believed that viral replication was too intimately involved with cellular processes for “magic bullets” specific for these pathogens to be much more than fantasy. This dogma has since passed on with the advent of clinically useful antiviral agents, but the success of these agents has borne yet another firmly held tenent: antiviral agents should selectivelyinteract with viral macromolecules (ie, these agents should not interfere with normal cellular metabolic processes). 1 This assumption certainly appears practical as well as logical since the cause of a given toxic side effect can often be traced to the disturbance of some fundamental cell function. A common mechanistic motif of nucleoside antiviral agents currently in clinical use is their metabolicconversion to the corresponding triphosphates and subsequent se-lective inhibition of viral nucleic acid polymerases. For example, zidovudine (3'-azidothymidine, AZT, Retrovir) is converted by cellular kinases to its 5'-triphosphate, and at therapeutic doses this metabolite selectively inactivates the reverse transcriptase of human immunodeficiency virus (HIV) while leaving cellular polymerases relatively unaf-fected. 2’3 Likewise, the triphosphate metabolite of acy-clovir (9-[(2-hydroxyethoxy) methyl] guanine, Zovirax) se-lectively inhibits the DNA polymerase of herpes simplex virus type I (HSV I). In fact, this guanosine analogue is doubly selective for virus-encoded enzymes since the drug requires herpesvirus thymidine kinase for efficient con-version to the active metabolite. 4 56'7