Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430

摘要

纤丝病毒科的病毒能在人类和非人类灵长目动物中引起严重出血热。死亡率极高，而且目前还没有疫苗或药物被批准用于纤丝病毒疾病的治疗。在这篇论文中，Sina Bavari及同事报告了在体外和体内对包括纤丝病毒如埃博拉病毒和苏丹病毒在内的高致病性病毒都有抗病毒活性的一种小分子病毒聚合酶抑制因子的发现。该化合物(BCX4430)是一种腺苷类似物，起一种非专性“链终止子”的作用。无论是口服还是肌内用药，它都能完全保护食蟹猴不受马尔堡病毒侵害，即便是在感染后48小时才用药。%Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.