Jones Thomas R, Lee Shi-Wu, Johann Stephen V, Razinkov Vladimir, Visalli Robert J, Feld Boris, Bloom Jonathan D, O'Connell John
Infectious Disease Section, Wyeth Research, Pearl River, New York 10965, USA.
J Virol. 2004 Feb;78(3):1289-300. doi: 10.1128/jvi.78.3.1289-1300.2004.
A novel 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.
通过使用全病毒感染细胞测定法筛选化学文库，鉴定出一种新型的人巨细胞病毒（HCMV）小分子抑制剂。合成化学研究产生了名为CFI02的类似物，该化合物的效力比最初的抑制剂提高了约100倍。CFI02在各种测定中的抑制浓度处于低纳摩尔范围。CFI02是一种选择性且有效的HCMV抑制剂；它对其他巨细胞病毒、甲型疱疹病毒或无关病毒没有活性。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中发生了足以赋予耐药性的突变。综合来看，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的细胞间传播。这是关于一种有效且选择性的CMV融合和细胞间传播小分子抑制剂的首次研究。
