Sun Wei, He Shihua, Martínez-Romero Carles, Kouznetsova Jennifer, Tawa Gregory, Xu Miao, Shinn Paul, Fisher Ethan, Long Yan, Motabar Omid, Yang Shu, Sanderson Philip E, Williamson Peter R, García-Sastre Adolfo, Qiu Xiangguo, Zheng Wei
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda MD 20892, USA.
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada.
Antiviral Res. 2017 Jan;137:165-172. doi: 10.1016/j.antiviral.2016.11.017. Epub 2016 Nov 24.
Although a group of FDA-approved drugs were previously identified with activity against Ebola virus (EBOV), most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann-Pick C1, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection.
尽管之前已鉴定出一组经美国食品药品监督管理局（FDA）批准的具有抗埃博拉病毒（EBOV）活性的药物，但其中大多数在临床上并无用处，因为它们在人体血液中的浓度不足以抑制EBOV感染。我们在EBOV进入试验中筛选了795种独特的三联药物组合。鉴定出两组三联药物组合，即托瑞米芬-甲氟喹-泊沙康唑和托瑞米芬-克拉霉素-泊沙康唑，它们能有效阻断EBOV进入，并进一步验证了对活EBOV感染的抑制作用。组合中各药物的浓度降低至临床相关水平。我们确定了这些药物的作用机制：对尼曼-匹克C1、酸性鞘磷脂酶和溶酶体钙释放的功能抑制。我们的研究结果确定了具有治疗EBOV感染潜力的药物组合。
