抗丙型肝炎病毒核苷酸前药 PSI-352938 的代谢激活。,Antimicrobial Agents and Chemotherapy

当前位置： X-MOL 学术 › Antimicrob. Agents Chemother. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

抗丙型肝炎病毒核苷酸前药 PSI-352938 的代谢激活。
Antimicrobial Agents and Chemotherapy ( IF 4.1 ) Pub Date : 2012-04-23 , DOI: 10.1128/aac.00530-12
Congrong Niu ₁ , Tatiana Tolstykh , Haiying Bao , Yeojin Park , Darius Babusis , Angela M Lam , Shalini Bansal , Jinfa Du , Wonsuk Chang , P Ganapati Reddy , Hai-Ren Zhang , Joseph Woolley , Li-Quan Wang , Piyun B Chao , Adrian S Ray , Michael J Otto , Michael J Sofia , Phillip A Furman , Eisuke Murakami

Affiliation

PSI-352938 是 β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine-5'-monophosphate 的新型环状磷酸酯前药，具有有效的抗 HCV 活性。为了抑制 NS5B RNA 依赖性 RNA 聚合酶，PSI-352938 必须代谢为活性三磷酸形式 PSI-352666。在与 PSI-352938 的体外孵育过程中，与克隆 A 丙型肝炎病毒 (HCV) 复制子细胞相比，原代肝细胞中形成了显着更多的 PSI-352666。进行代谢和生化分析以确定 PSI-352938 激活的分子机制。第一步，即去除 3',5'-环状磷酸基团上的异丙基，发现依赖于细胞色素 P450 (CYP) 3A4，而其他 CYP 同工型无法催化反应。第二步，打开环状磷酸环，由磷酸二酯酶 (PDE) 2A1、5A、9A 和 11A4 催化，这些酶均已知在肝脏中表达。这些酶在 PSI-352938 激活中的作用在原代人肝细胞中得到证实，其中前药激活被 CYP3A4 和 PDE 抑制剂降低。第三步，去除核碱基上的 O(6)-乙基，显示由腺苷脱氨酶样蛋白 1 催化。产生的单磷酸酯被鸟苷酸激酶连续磷酸化为二磷酸和三磷酸 PSI-352666 1 和核苷二磷酸激酶，分别。此外，在原代肝细胞中观察到核苷代谢物的形成，并且 ecto-5'-核苷酸酶能够使单磷酸代谢物去磷酸化。由于 CYP3A4 在肝脏中高表达，

"点击查看英文标题和摘要"

Metabolic activation of the anti-hepatitis C virus nucleotide prodrug PSI-352938.

PSI-352938 is a novel cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine-5'-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, PSI-352938 must be metabolized to the active triphosphate form, PSI-352666. During in vitro incubations with PSI-352938, significantly larger amounts of PSI-352666 were formed in primary hepatocytes than in clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays were performed to define the molecular mechanism of PSI-352938 activation. The first step, removal of the isopropyl group on the 3',5'-cyclic phosphate moiety, was found to be cytochrome P450 (CYP) 3A4 dependent, with other CYP isoforms unable to catalyze the reaction. The second step, opening of the cyclic phosphate ring, was catalyzed by phosphodiesterases (PDEs) 2A1, 5A, 9A, and 11A4, all known to be expressed in the liver. The role of these enzymes in the activation of PSI-352938 was confirmed in primary human hepatocytes, where prodrug activation was reduced by inhibitors of CYP3A4 and PDEs. The third step, removal of the O(6)-ethyl group on the nucleobase, was shown to be catalyzed by adenosine deaminase-like protein 1. The resulting monophosphate was consecutively phosphorylated to the diphosphate and to the triphosphate PSI-352666 by guanylate kinase 1 and nucleoside diphosphate kinase, respectively. In addition, formation of nucleoside metabolites was observed in primary hepatocytes, and ecto-5'-nucleotidase was able to dephosphorylate the monophosphate metabolites. Since CYP3A4 is highly expressed in the liver, the CYP3A4-dependent metabolism of PSI-352938 makes it an effective liver-targeted prodrug, in part accounting for the potent antiviral activity observed clinically.

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南