Increased antiviral activity of 1-O-hexadecyloxypropyl-[ 2-14C] cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism
Increased antiviral activity of 1-O-hexadecyloxypropyl-[ 2-14C] cidofovir in MRC-5 human lung fibroblasts is explained by unique cellular uptake and metabolism
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DOI：
10.1124/mol.63.3.678
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发表时间：
2003-03-01
影响因子：
3.6
通讯作者：
Hostetler, KY
中科院分区：
文献类型：
--
作者：
Aldern, KA;Ciesla, SL;Hostetler, KY
最近，人们对寻找口服抗天花药物重新产生了兴趣。西多福韦（CDV）给予胃肠外注射已被证明可以防止致命的痘病毒感染。我们一直对CDV口服活性衍生物的合成和评价感兴趣。先前的研究表明，CDV和环状西多福韦（cCDV）类似物1-O-癸氧基丙基-CDV（HDP-CDV）和1-O-十六烷氧基丙基-cCDV（HDP-cCDV）显示出与未修饰的核苷相比抗正痘病毒、牛痘病毒和牛痘病毒感染的细胞的抗病毒活性增加>100倍。与CDV相反，HDP-CDV是口服生物可利用的，并且已经报道在小鼠中的致死性牛痘病毒感染中具有口服活性。为了评估HDP-CDV体外抗病毒活性增加的代谢基础，我们研究了C-14标记的CDV、cCDV及其烷氧基烷醇酯HDP-CDV和HDP-cCDV的细胞摄取和合成代谢。体外培养的MRC-5人肺成纤维细胞能迅速摄取HDP-CDV和HDP-cCDV，但摄取CDV和cCDV的速度要慢得多。细胞代谢物的分析显示，HDP-CDV的活性抗病毒化合物二磷酸西多福韦（CDV-DP）的水平比CDV观察到的水平高>100倍。当细胞暴露于HDP-CDV时，CDV-DP的细胞内半衰期为10天，而当细胞暴露于CDV时报道为2.7天。HDP-CDV似乎通过与细胞膜磷脂的快速结合来规避差的细胞摄取，而CDV摄取通过缓慢的流体内吞过程进行。
Recently, there has been renewed interest in finding orally active drugs against smallpox. Cidofovir (CDV) given by parenteral injection has been shown to protect against lethal poxvirus infection. We have been interested in the synthesis and evaluation of orally active derivatives of CDV. Previous studies showed that the CDV and cyclic cidofovir (cCDV) analogs 1-Ohexa-decyloxypropyl-CDV (HDP-CDV) and 1-O-hexadecyloxypropyl-cCDV (HDP-cCDV), show >100-fold increases in antiviral activity versus the unmodified nucleosides against cells infected with orthopoxviruses, cowpox, and vaccinia virus. In contrast to CDV, HDP-CDV is orally bioavailable and has been reported to be orally active in lethal cowpox virus infection in mice. To assess the metabolic basis for the increased antiviral activity of HDP-CDV in vitro, we studied the cellular uptake and anabolic metabolism of C-14-labeled CDV, cCDV, and their alkoxyalkanol esters HDP-CDV and HDP-cCDV. HDP-CDV and HDP-cCDV were taken up rapidly by MRC-5 human lung fibroblasts in vitro, but uptake of CDV and cCDV was much slower. Analysis of cellular metabolites showed that levels of cidofovir diphosphate (CDV-DP), the active antiviral compound, were >100 times greater with HDP-CDV than levels observed with CDV. When cells were exposed to HDP-CDV, the intracellular half-life of CDV-DP was 10 days versus 2.7 days reported when cells are exposed to CDV. HDP-CDV seems to circumvent poor cellular uptake by rapid association with cellular membrane phospholipids, whereas CDV uptake proceeds via the slow process of fluid endocytosis.