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Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01009 Marco Derudas 1 , Christophe Vanpouille 2 , Davide Carta 1 , Sonia Zicari 2 , Graciela Andrei 3 , Robert Snoeck 3 , Andrea Brancale 1 , Leonid Margolis 2 , Jan Balzarini 3 , Christopher McGuigan 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01009 Marco Derudas 1 , Christophe Vanpouille 2 , Davide Carta 1 , Sonia Zicari 2 , Graciela Andrei 3 , Robert Snoeck 3 , Andrea Brancale 1 , Leonid Margolis 2 , Jan Balzarini 3 , Christopher McGuigan 1
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Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed.
中文翻译：
虚拟筛选作为潜在抗病毒药的阿昔洛韦衍生物：新无环核苷肽的设计，合成和生物学评估
根据我们对无环鸟苷（ACV）磷酸盐前药的抗人免疫缺陷病毒（HIV）活性的发现，我们在此报告了ProTide方法应用于一系列无环核苷的用途，旨在鉴定新型和选择性抗病毒剂，特别是抗HIV代理商。本研究中使用的无环核苷类似物通过使用HIV逆转录酶（RT），腺苷酸/鸟苷酸激酶和人DNA聚合酶γ的虚拟筛选进行鉴定。总共合成了39种新的磷酸盐前药，并针对HIV-1（体外和离体人类扁桃体组织系统）和人类疱疹病毒进行了评估。几种ProTide化合物在低微摩尔范围内显示出对HIV-1的显着效力，而母体核苷则无效。另外，观察到明显抑制疱疹病毒复制。
更新日期：2017-09-20
中文翻译：
虚拟筛选作为潜在抗病毒药的阿昔洛韦衍生物：新无环核苷肽的设计，合成和生物学评估
根据我们对无环鸟苷（ACV）磷酸盐前药的抗人免疫缺陷病毒（HIV）活性的发现，我们在此报告了ProTide方法应用于一系列无环核苷的用途，旨在鉴定新型和选择性抗病毒剂，特别是抗HIV代理商。本研究中使用的无环核苷类似物通过使用HIV逆转录酶（RT），腺苷酸/鸟苷酸激酶和人DNA聚合酶γ的虚拟筛选进行鉴定。总共合成了39种新的磷酸盐前药，并针对HIV-1（体外和离体人类扁桃体组织系统）和人类疱疹病毒进行了评估。几种ProTide化合物在低微摩尔范围内显示出对HIV-1的显着效力，而母体核苷则无效。另外，观察到明显抑制疱疹病毒复制。
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