Strang Blair L
Institute for Infection & Immunity, St George's, University of London, London, UK; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Antiviral Res. 2017 Aug;144:21-26. doi: 10.1016/j.antiviral.2017.05.004. Epub 2017 May 10.
Public-private partnerships allow many previously unavailable compounds to be screened for antiviral activity. Here a screening method was used to identify an oxindole compound, RO0504985, from a Roche kinase inhibitor library that inhibited human cytomegalovirus (HCMV) protein production. RO0504985 was previously described as an inhibitor of cyclin-dependent kinase 2 (CDK2). However, using kinase selectivity assays it was found that RO0504985 was an inhibitor of several CMGC group kinase proteins, including CDK2. Using virus yield reduction assays it was observed that RO0504985 inhibited replication of different HCMV strains at low micromolar concentrations. Western blotting was used to investigate how RO0504985 inhibited HCMV replication. Treatment of HCMV infected cells with RO0504985 inhibited production of the immediate early viral IE2 proteins and the late viral protein pp28. Thus, RO0504985 inhibited HCMV replication by preventing production of specific HCMV proteins necessary for virus replication.
公私合营伙伴关系使许多以前无法获得的化合物能够接受抗病毒活性筛选。在此,我们使用一种筛选方法从罗氏激酶抑制剂文库中鉴定出一种氧化吲哚化合物RO0504985,该化合物可抑制人巨细胞病毒(HCMV)蛋白的产生。RO0504985以前被描述为细胞周期蛋白依赖性激酶2(CDK2)的抑制剂。然而,通过激酶选择性测定发现,RO0504985是几种CMGC组激酶蛋白的抑制剂,包括CDK2。通过病毒产量降低试验观察到,RO0504985在低微摩尔浓度下可抑制不同HCMV毒株的复制。采用蛋白质免疫印迹法研究RO0504985抑制HCMV复制的机制。用RO0504985处理HCMV感染的细胞可抑制病毒立即早期IE2蛋白和晚期病毒蛋白pp28的产生。因此,RO0504985通过阻止产生病毒复制所需的特定HCMV蛋白来抑制HCMV复制。