Zalicus Inc., 245 First Street, Cambridge, MA 02142, USA.
Sci Transl Med. 2013 Jun 19;5(190):190ra79. doi: 10.1126/scitranslmed.3005471.
Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)- and ex-US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections.
埃博拉病毒作为生物武器，在零星爆发期间以及受感染个体从流行地区意外输入的情况下，仍然对平民和军人构成重大威胁。目前，尚无经批准的治疗药物可用于治疗或预防埃博拉病毒感染。因此，我们对美国食品和药物管理局（FDA）和非美国批准的药物进行了体外筛选，并选择了分子探针，以确定对扎伊尔埃博拉病毒（EBOV）具有抗病毒活性的药物。通过该筛选，我们确定了一组选择性雌激素受体调节剂（SERMs），包括氯米酚和托瑞米芬，它们是 EBOV 感染的有效抑制剂。这两种 SERM 在体内小鼠感染模型中均证实具有抗 EBOV 活性。即使在没有检测到雌激素受体表达的情况下，这种抗 EBOV 活性仍然存在，并且两种 SERM 均在内化后抑制病毒进入，这表明氯米酚和托瑞米芬并非通过与雌激素受体相关的经典途径发挥作用。相反，这种反应似乎是一种非靶向效应，其中化合物干扰病毒进入的晚期步骤，并可能影响融合的触发。这些数据支持筛选现成的批准药物，以确定针对埃博拉病毒和其他传染病的治疗方法。本报告中描述的 SERM 化合物是一类可立即采取行动的批准药物，可以重新用于治疗丝状病毒感染。
