Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years.
Advanced Prodrug Strategies in Nucleoside and Non-Nucleoside Antiviral Agents: A Review of the Recent Five Years.
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DOI：
10.3390/molecules22101736
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发表时间：
2017-10-16
期刊：
影响因子：
--
通讯作者：
Karaman R
中科院分区：
文献类型：
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作者：
Sinokrot H;Smerat T;Najjar A;Karaman R
背景资料：不良的药代动力学特征和耐药性是目前使用的抗病毒药物的两个主要缺点，因此使它们成为研究的极好目标，特别是在存在病毒大流行如HIV和丙型肝炎的情况下。研究方法：在本综述中所涵盖的研究中采用的策略按合成的药物类型分为酯类前药、靶向递送前药、大分子前药、其他核苷缀合物和非核苷药物。结果：利用酯前体药物合成方法，合成了一种新的异丙酯前体药物，具有很强的HIV整合酶抑制剂活性。此外，采用靶向递送前药扎那米韦和缬氨酸酯前药制备并显示扎那米韦的单独递送。此外，VivaGel是一种树枝状大分子前药，被发现非常有效，目前正在进行临床试验。结论：在所采用的所有策略（酯、靶向递送、大分子、前药和核苷类似物以及非核苷类似物前药）中，最有希望的是核苷类似物和大分子前药。大分子前体药物VivaGel通过两种机制起作用：包膜介导和受体介导的破坏。核苷酸类似物在过去的几年里见证了生产时代。肝炎的非干扰素治疗（通过NS5A的直接抑制剂）的时代已经到来。
Background: Poor pharmacokinetic profiles and resistance are the main two drawbacks from which currently used antiviral agents suffer, thus make them excellent targets for research, especially in the presence of viral pandemics such as HIV and hepatitis C. Methods: The strategies employed in the studies covered in this review were sorted by the type of drug synthesized into ester prodrugs, targeted delivery prodrugs, macromolecular prodrugs, other nucleoside conjugates, and non-nucleoside drugs. Results: Utilizing the ester prodrug approach a novel isopropyl ester prodrug was found to be potent HIV integrase inhibitor. Further, employing the targeted delivery prodrug zanamivir and valine ester prodrug was made and shown a sole delivery of zanamivir. Additionally, VivaGel, a dendrimer macromolecular prodrug, was found to be very efficient and is now undergoing clinical trials. Conclusions: Of all the strategies employed (ester, targeted delivery, macromolecular, protides and nucleoside analogues, and non-nucleoside analogues prodrugs), the most promising are nucleoside analogues and macromolecular prodrugs. The macromolecular prodrug VivaGel works by two mechanisms: envelope mediated and receptor mediated disruption. Nucleotide analogues have witnessed productive era in the recent past few years. The era of non-interferon based treatment of hepatitis (through direct inhibitors of NS5A) has dawned.