Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule
Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule
复制标题
DOI：
10.1128/jvi.78.3.1289-1300.2004
复制
发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
O'Connell, J
中科院分区：
文献类型：
--
作者：
Jones, TR;Lee, SW;O'Connell, J
利用全病毒感染细胞试验筛选化学文库，鉴定出人巨细胞病毒（HCMV）小分子抑制剂。合成化学的努力产生了被命名为CFI02的类似物，这种化合物的效力比最初的抑制剂提高了约100倍。CFI02的抑制浓度在低纳摩尔范围内。CFI02是一种选择性和有效的HCMV抑制剂；对其他巨细胞病毒、甲疱疹病毒或无关病毒无活性。作用机制研究表明，CFI02在复制周期的早期起作用，抑制病毒粒子包膜与细胞质膜的融合。对CFI02耐药的突变体在丰富的病毒粒子包膜糖蛋白B中发生突变，足以赋予耐药性。综上所述，数据表明CFI02抑制糖蛋白b介导的HCMV病毒粒子融合。此外，CFI02抑制HCMV的细胞间扩散。这是首次研究一种有效的选择性CMV融合和细胞-细胞扩散的小分子抑制剂。
small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.