Characterization of virus strains resistant to the herpes virus helicase-primase inhibitor ASP2151 (Amenamevir)
Characterization of virus strains resistant to the herpes virus helicase-primase inhibitor ASP2151 (Amenamevir)
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DOI：
10.1016/j.bcp.2012.05.020
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发表时间：
2012-08-15
影响因子：
5.8
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Chono, Koji;Katsumata, Kiyomitsu;Suzuki, Hiroshi
ASP 2151是一种靶向单纯疱疹病毒（HSV）-1、HSV-2和水痘-带状疱疹病毒（VZV）解旋酶引发酶复合物的抗疱疹药物。我们根据测序分析、生长、致病性和药敏试验的结果，对ASP 2151耐药HSV-1和HSV-2变体或突变体进行了表征，确定了导致ASP 2151耐药突变体解旋酶和引发酶亚基氨基酸变化的几个单碱基对置换。解旋酶亚基中的氨基酸改变聚集在HSV-1和HSV-2的UL 5解旋酶基因中的解旋酶基序IV附近，而在ASP 2151耐药HSV-1突变体中发现了与敏感性降低相关的引发酶亚基取代R367 H。然而，尽管ASP 2151耐药HSV突变体对现有抗疱疹药物的敏感性与野生型HSV毒株相当，但与亲本毒株相比，ASP 2151耐药HSV突变体的体外生长能力和体内致病性减弱。总之，我们目前的研究结果表明，与HSV-1和HSV-2对ASP 2151的亲和性降低相关的重要氨基酸取代存在于解旋酶引发酶复合物的解旋酶和引发酶亚基中，并且该复合物中针对ASP 2151的突变可能导致病毒复制和致病性缺陷。(C)2012 Elsevier Inc. All rights reserved.
ASP2151 is an antiherpes agent targeting the helicase primase complex of herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV). We characterized the ASP2151-resistant HSV-1 and HSV-2 variants or mutants based on findings from sequencing analysis, growth, pathogenicity, and susceptibility testing, identifying several single base-pair substitutions resulting in amino acid changes in the helicase and primase subunit of ASP2151-resistant mutants. Amino acid alterations in the helicase subunit were clustered near helicase motif IV in the UL5 helicase gene of both HSV-1 and HSV-2, while the primase subunit substitution associated with reduced susceptibility, R367H, was found in ASP2151-resistant HSV-1 mutants. However, while susceptibility in the ASP2151-resistant HSV mutants to existing antiherpes agents was equivalent to that in wild-type HSV strains, ASP2151-resistant HSV mutants showed attenuated in vitro growth capability and in vivo pathogenicity compared with the parent strains. Taken together, our present findings demonstrated that important amino acid substitutions associated with reduced susceptibilities of HSV-1 and HSV-2 to ASP2151 exist in both the helicase and primase subunits of the helicase primase complex, and that mutations in this complex against ASP2151 might confer defects in viral replication and pathogenicity. (C) 2012 Elsevier Inc. All rights reserved.