Balzarini J
K.U.L.-Rega Instituut, Leuven, België.
Verh K Acad Geneeskd Belg. 1991;53(1):61-98.
The antiviral mechanism of action and intracellular metabolism of 2',3'-dideoxycytidine (ddCyd), 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) has been investigated. Marked differences in the affinity of these anti-HIV compounds for their activating (phosphorylating) enzymes, and the eventual intracellular levels of their active 5'-triphosphate metabolites were discovered. Moreover, new approaches were developed to manipulate the metabolism of these products in such a way that combination of ddCyd with thymidine, and 2',3'-dideoxynosine with ribavirin resulted in an enhanced antiretroviral effect of the test compounds in vitro and/or in vivo. Several metabolic and kinetic properties of AZT and D4T proved highly relevant to perform or modify the treatment modalities of AIDS patients with these chemotherapeutics. A novel class of acyclic purine nucleotide phosphonate derivatives endowed with potent and selective anti-HIV activity has been developed. The prototype compound is 9-(2-phosphonylmethoxyethyl)adenine (PMEA). PMEA proved to have a potent antiretroviral activity in a number of retrovirus models in vivo. Furthermore, a unique administration schedule of PMEA in retrovirus infections has been proposed, in which the antiretroviral properties of PMEA are clearly superior and distinguished from those of other chemotherapeutics such as AZT. The metabolic and kinetic properties of PMEA and its phosphorylated metabolites have been investigated. Our data provide a better and profound insight in the antiretroviral activity and the molecular and biochemical bases for the mechanism or action of the drug.
已对2′,3′-双脱氧胞苷（ddCyd）、3′-叠氮基-2′,3′-双脱氧胸苷（AZT）和2′,3′-双脱氢-2′,3′-双脱氧胸苷（D4T）的抗病毒作用机制及细胞内代谢进行了研究。发现这些抗HIV化合物对其激活（磷酸化）酶的亲和力以及其活性5′-三磷酸代谢产物最终的细胞内水平存在显著差异。此外，还开发了新方法来调控这些产物的代谢，使得ddCyd与胸苷、2′,3′-双脱氧肌苷与利巴韦林联合使用时，受试化合物在体外和/或体内的抗逆转录病毒作用增强。AZT和D4T的几种代谢和动力学特性被证明与使用这些化疗药物治疗艾滋病患者的方式实施或调整高度相关。已开发出一类具有强效和选择性抗HIV活性的新型无环嘌呤核苷酸膦酸酯衍生物。原型化合物是9-(2-膦酰甲氧基乙基)腺嘌呤（PMEA）。PMEA在多种体内逆转录病毒模型中被证明具有强效抗逆转录病毒活性。此外，还提出了PMEA在逆转录病毒感染中的独特给药方案，其中PMEA的抗逆转录病毒特性明显优于其他化疗药物如AZT，并与之有所区别。已对PMEA及其磷酸化代谢产物的代谢和动力学特性进行了研究。我们的数据为该药物的抗逆转录病毒活性以及作用机制的分子和生化基础提供了更好且更深入的见解。
