Preclinical development of a Nipah Virus inhibitor

项目摘要 SARS-CoV-2导致开发更多新出现病毒的治疗方法的紧迫性增加，并 有可能提供更广泛的抗病毒药物，以预测大流行病毒。尼帕病毒(Nipah Virus)是一种 蝙蝠传播的病原体(副粘病毒科)，导致急性并通常是致命的(最近在印度爆发了 确诊病例死亡率~70%)目前没有FDA治疗的呼吸系统和神经系统疾病 批准的治疗。很少有小分子抗病毒药物显示出抗病毒活性。 [和合]无论在体外还是在体内。这些药物包括法维拉韦(EC9015.87-123.8微米)，它导致在 在非洲每天静脉(IV)给药的仓鼠模型和雷米昔韦(EC90 50-100 NM) 绿猴(AGM)模型导致其存活。我们最近鉴定了咯萘啶的抗病毒活性。 (EC50=65.57 NM，CC50 3.65微米)，适用于Niv(马来西亚株，专利号17/092,058)。我们还表明， 咯萘啶在体外具有抗埃博拉病毒的作用，在小鼠和豚鼠体内也有作用。另外， 咯萘啶具有良好的体外抗马尔堡病毒活性和体内抗病毒效果。 小鼠感染SARS-CoV-2。我们最近已经证明，咯萘啶是溶酶体亲和性的，与埃博拉病毒结合 并能减轻SARS-CoV-2诱导的小鼠炎性细胞因子风暴。我们现在 建议在进行疗效研究之前评估口服最大耐受量和药代动力学 在Niv的仓鼠模型中。如果我们成功地证明了体内的疗效，我们将申请一种孤儿药物 FDA的指定和前IND。如果我们在第一阶段表现出统计上显着的疗效，那么我们将 使用NIV的非洲绿猴模型在第二阶段进行药效测试，执行IND启用 毒理学研究和生产GMP级丙酸丙二醇酯。我们的最终目标是带来一个 美国和其他国家可以储存的针对新城疫病毒的上市治疗，为未来做准备 疫情爆发。

Project Summary SARS-CoV-2 has led to an increased urgency to develop treatments for additional emerging viruses and potentially provide broader spectrum antivirals in order to anticipate pandemic viruses. Nipah virus (NiV) is a bat-borne pathogen (family Paramyxoviridae) that results in acute and often fatal (recent outbreaks in India have demonstrated case fatality ~70%) respiratory and neurological disease for which there is currently no FDA approved treatment. There have been very few small molecule antivirals that have demonstrated activity against NiV either in vitro or in vivo. These include favipiravir (EC90 15.87- 123.8 µM) which resulted in survival in the hamster model and remdesivir (EC90 50-100 nM) when dosed daily by the intravenous (IV) route in the African green monkey (AGM) model resulting in their survival. We recently identified the antiviral activity of pyronaridine (EC50 = 65.57 nM and CC50 3.65 µM) for NiV (Malaysia strain, Patent No. 17/092,058). We have also shown that pyronaridine has efficacy against Ebola in vitro and efficacy in vivo in mice and guinea pig. Additionally, pyronaridine has demonstrated promising activity in vitro against Marburg virus and in vivo efficacy against SARS-CoV-2 in mice. We have recently shown that pyronaridine is lysosomotropic and binds to the Ebola glycoprotein as well as decreases the inflammatory cytokine storm in mice induced by SARS-CoV-2. We now propose to assess the oral maximum tolerated dose and pharmacokinetics prior to performing efficacy studies in the hamster model of NiV. If we are successful in demonstrating in vivo efficacy, we will file an orphan drug designation and a preIND with the FDA. If we demonstrate statistically significant efficacy in Phase I we will then perform efficacy testing in Phase II using the African Green Monkey model for NiV, perform IND enabling toxicology studies and manufacture GMP grade pyronaridine tertraphosphate. Our ultimate aim is to bring a treatment to market for NiV which can be stockpiled by the USA and other countries in preparation for future outbreaks.