PANACEA Broad-spectrum Antiviral Therapeutics

尽管新出现的病毒和NIAID A-C类优先病原体名单上的病毒引起了极大的关注，但针对这些病毒的预防或治疗药物相对较少，而且大多数确实存在，具有高度的病原体特异性或具有不良副作用或其他缺点。我们已经开发出一种全新的、非常广谱的抗病毒治疗/预防药物，它有可能彻底改变病毒感染的治疗，包括由新出现的A-C类和常见的临床病原体引起的病毒感染。 我们的dsRNA(双链RNA)激活的caspase(DAC)方法选择性地诱导含有任何病毒dsRNA的细胞凋亡，快速杀死受感染的细胞，而不损害未受感染的细胞。我们之前已经创造了一种DAC，并证明了它是无毒的，在10种哺乳动物细胞类型中对10种不同的病毒有效。我们还证明了它对小鼠无毒，并将小鼠从致命的H1N1流感挑战中拯救出来。A-C类名单上的大量病毒属于阿雷纳病毒、布尼亚病毒和黄病毒家族，我们以前没有对这些病毒家族进行过DAC测试。 因此，这项提议的实验重点是测试DAC对这些病毒家族中具有代表性的成员的作用。具体目标是： 1.证明在多种哺乳动物细胞类型中对具有代表性的成员的有效性 阿雷纳病毒、布尼亚病毒和黄病毒家族。 2.进行DAC体内药代动力学分析和免疫原性评价。 3.使用体外试验中最好的挑战病毒，在致死小鼠模型中展示抗病毒效果。 这些目标的成功将证明DAC在治疗阿拉伯病毒、布尼亚病毒和黄病毒方面的潜力，并为进一步利用其他病毒和动物模型进行试验铺平道路。这项工作将极大地推动DAC作为一种安全、广谱的治疗/预防NIAID优先事项和新出现的病毒病原体的最终用途，填补现有疗法中的一大空白，并直接支持NERCE的使命。

Although there is great concern over emerging viruses and viruses on the NIAID category A-C priority pathogen lists, there are relatively few prophylactics or therapeutics for these viruses, and most which do exist are highly pathogen-specific or have undesirable side effects or other disadvantages. We have developed a radically new and very broad-spectrum antiviral therapeutic/prophylactic that has the potential to revolutionize the treatment of viral infections, including those due to emerging, category A-C, and common clinical pathogens. Our dsRNA (double-stranded RNA) activated caspase (DAC) approach selectively induces apoptosis in cells containing any viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have previously created a DAC and shown that it is nontoxic and effective against 10 different viruses in 10 mammalian cell types. We have also demonstrated that it is nontoxic in mice and rescues mice from a lethal H1N1 influenza challenge. A large number of viruses on the category A-C lists belong to the arenavirus, bunyavirus, and flavivirus families, virus families against which we have not previously tested DAC. Therefore, the experimental focus of this proposal is to test DAC against representative members of these virus families. The specific aims are to: 1. Demonstrate efficacy in multiple mammalian cell types against representative members of the arenavirus, bunyavirus, and flavivirus families. 2. Perform DAC pharmacokinetic analyses and assess DAC immunogenicity in vivo. 3. Demonstrate antiviral efficacy in a lethal mouse model using the best challenge virus from the in vitro trials. Success in these aims should demonstrate the potential of DAC to treat arenaviruses, bunyaviruses, and flaviviruses and pave the way for further trials with additional viruses and animal models. This work should greatly advance DAC toward ultimate utility as a safe, broad-spectrum therapeutic/prophylactic for NIAID priority and emerging viral pathogens, filling a large gap in existing therapeutics and directly supporting NERCE's mission.