Center for Drug Design, University of Minnesota, 312 Church St SE, MMC 204, Minneapolis, MN, 55125, USA.
Center for Drug Design, University of Minnesota, 312 Church St SE, MMC 204, Minneapolis, MN, 55125, USA.
Antiviral Res. 2018 Apr;152:10-17. doi: 10.1016/j.antiviral.2018.01.015. Epub 2018 Feb 6.
Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus production. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compounds featuring a chelating triad motif. Previously, we developed a novel ELISA approach to screen for pUL89 inhibitors. In this report, we used the ELISA to identify 3-hydroxypyrimidine-2,4-dione as a promising scaffold for pUL89 inhibitor development. Several potent pUL89 inhibitors yielded low micromolar IC values in the enzymatic assay and low micromolar EC values for inhibition of HCMV replication. Two representative compounds inhibitory effects depended upon metal ions and occurred late in virus replication consistent with pUL89 inhibitors in infected cells.
人巨细胞病毒末端酶复合物在基因组包装和粒子组装过程中将连接的基因组病毒 DNA 切割成单位长度。末端酶复合物的 ATP 酶和内切核酸酶活性由病毒蛋白 pUL89 提供。pUL89 是一个有吸引力的药物靶点，因为其活性对于产生感染性病毒是必需的。pUL89 羧基末端的一个结构域具有核糖核酸酶 H/整合酶样折叠和内切核酸酶活性，可被具有螯合三齿基序的化合物抑制。先前，我们开发了一种新的 ELISA 方法来筛选 pUL89 抑制剂。在本报告中，我们使用 ELISA 鉴定 3-羟基嘧啶-2,4-二酮作为 pUL89 抑制剂开发的有前途的支架。几种有效的 pUL89 抑制剂在酶测定中产生了低微摩尔 IC 值，并且对 HCMV 复制的抑制具有低微摩尔 EC 值。两种代表性化合物的抑制作用取决于金属离子，并且在病毒复制的晚期发生，与感染细胞中的 pUL89 抑制剂一致。
