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 IC₅₀ values in the enzymatic assay and low micromolar EC₅₀ 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.

人类巨细胞病毒末端酶复合物在基因组包装和颗粒组装过程中将连接体基因组病毒DNA切割成单位长度。病毒蛋白pUL89提供了末端酶复合物ATPase和核酸内切酶的活性。pUL89是一种有吸引力的药物靶标，因为其活性是生产感染性病毒所必需的。位于pUL89 C末端的结构域具有RNase H /整合酶样折叠和内切核酸酶活性，这些活性可以被具有螯合三联体基序的化合物抑制。以前，我们开发了一种新颖的ELISA方法来筛选pUL89抑制剂。在本报告中，我们使用ELISA鉴定了3-羟基嘧啶-2,4-二酮是pUL89抑制剂开发的有希望的支架。几种有效的pUL89抑制剂可产生低微摩尔IC ₅₀在酶促测定中的值和低微摩尔EC ₅₀值可抑制HCMV复制。两种代表性化合物的抑制作用取决于金属离子，并且在病毒复制后期发生，与感染细胞中的pUL89抑制剂一致。