Holý A, Votruba I, Merta A, Cerný J, Veselý J, Vlach J, Sedivá K, Rosenberg I, Otmar M, Hrebabecký H
Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Prague.
Antiviral Res. 1990 Jun;13(6):295-311. doi: 10.1016/0166-3542(90)90014-x.
Several N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) (HPMP) and N-(2-phosphonylmethoxyethyl) (PME) derivatives of purine bases (adenine, guanine, 2-aminoadenine, 3-deazaadenine) and cytosine inhibit the growth of various DNA viruses. PME-derivatives (PMEA, PMEG and PMEDAP) are also active against retroviruses. Both types of nucleotide analogues undergo phosphorylation by cellular nucleotide kinases to their mono- and diphosphates. The phosphorylation with crude extracts of L-1210 cells is potentiated by an ATP-regenerating system. HPMPA is phosphorylated faster than PMEA with or without the ATP-regenerating system. The HPMP and PME analogues inhibit several virus-encoded target enzymes and their cellular counterparts: (1) HSV-1 DNA polymerase is inhibited by the diphosphates of the PME series; the virus-encoded enzyme is more sensitive than HeLa DNA pol alpha and beta. PMEApp terminates the growing DNA chain; it specifically replaces dATP. HPMPApp also acts as an alternative substrate of dATP, but, in contrast with PMEApp, it permits limited chain growth. (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp. The enzyme isolated from a PMEA-resistant HSV-1 mutant proved less sensitive to PMEApp, hydroxyurea and HPMPApp. (3) Diphosphates of PME derivatives efficiently inhibit AMV(MAV) reverse transcriptase. (4) The purine HPMP and PME analogues and, even more so, their monophosphate derivatives inhibit purine nucleoside phosphorylase from L-1210 cells.
嘌呤碱基（腺嘌呤、鸟嘌呤、2-氨基腺嘌呤、3-脱氮腺嘌呤）和胞嘧啶的几种N-（S）-（3-羟基-2-膦酰甲氧基丙基）（HPMP）及N-（2-膦酰甲氧基乙基）（PME）衍生物可抑制多种DNA病毒的生长。PME衍生物（PMEA、PMEG和PMEDAP）对逆转录病毒也有活性。这两类核苷酸类似物均可被细胞核苷酸激酶磷酸化为其一磷酸酯和二磷酸酯。L-1210细胞粗提物的磷酸化作用可被ATP再生系统增强。无论有无ATP再生系统，HPMPA的磷酸化速度都比PMEA快。HPMP和PME类似物可抑制几种病毒编码的靶酶及其细胞内对应物：（1）PME系列的二磷酸酯可抑制单纯疱疹病毒1型（HSV-1）DNA聚合酶；病毒编码的该酶比HeLa细胞的DNA聚合酶α和β更敏感。PMEApp可终止正在延长的DNA链；它可特异性取代dATP。HPMPApp也可作为dATP的替代底物，但与PMEApp不同的是，它允许有限的链延长。（2）这两个系列的二磷酸酯均可抑制HSV-1核糖核苷酸还原酶；HPMPApp和PMEApp对CDP还原为dCDP的抑制作用最强。从一株对PMEA耐药的HSV-1突变株中分离出的该酶对PMEApp、羟基脲和HPMPApp的敏感性较低。（3）PME衍生物的二磷酸酯可有效抑制禽成髓细胞瘤病毒（AMV）（MAV）逆转录酶。（4）嘌呤类HPMP和PME类似物，尤其是它们的一磷酸酯衍生物，可抑制L-1210细胞的嘌呤核苷磷酸化酶。
