Antiviral Drugs for Lassa Fever Virus

描述(由申请人提供)：出血热病毒是严重的世界性健康问题，也是潜在的生物武器。尤其是拉沙热病毒，每年感染西非数十万人，有意无意地将这种病原体出口到该区域以外，对世界发达国家构成严重风险。CDC和NIAID已将拉沙热病毒确定为A类优先病原体，这表明对公共卫生的威胁程度最高。我们生物防御计划的目的是开发安全有效的药物来预防和治疗由A类病毒引起的疾病。为此，筛选了一个庞大而多样的小分子化合物文库，以确定针对基本的LassA表面糖蛋白的抑制剂，从而阻止病毒进入宿主细胞。许多这些有效的抗病毒化合物及其相关类似物显示了信息丰富的化学结构-生物活性关系(SAR)。第二阶段提案的目标是将这些化合物推向临床开发，为最有力的候选药物提交研究新药(IND)的申请，并在需要时确定至少一个额外的临床前候选药物作为潜在的后备化合物。先导化合物将通过效力、毒性、新陈代谢和药代动力学标准进行优化。表现出可接受特征的化合物将在拉沙热动物模型中进行疗效评估。这些实验将首先在豚鼠身上进行，然后在非人类灵长类动物中进一步测试有效化合物。此外，抗病毒作用的机制将直接和通过对潜在的病毒逃逸突变体的检查来探索。含有异源包膜蛋白的复制缺陷逆转录病毒，如拉沙热病毒糖蛋白(病毒伪型)，将被用来评估复合效力和作用机制；这些实验可以在生物安全二级(BSL-2)条件下进行。结果将在BSL-4设施中使用正宗拉沙热病毒进行验证；使用拉沙热病毒的动物研究也将在BSL-4设施中进行。

DESCRIPTION (provided by applicant): Hemorrhagic fever viruses are of serious worldwide health concern as well as potential biological weapons. Lassa fever virus in particular annually infects several hundred thousand individuals in West Africa, and the export of this pathogen outside of this region, either intentionally or unintentionally, presents a serious risk to the developed countries of the world. The CDC and NIAID have identified Lassa fever virus as a Category A priority pathogen, indicating the highest degree of threat to public health. The purpose of our biodefense program is to develop safe and effective drugs for preventing and treating diseases caused by Category A viruses. To that end, a large and diverse library of small molecule compounds was screened to identify inhibitors that target the essential Lassa surface glycoprotein and thus block viral entry into the host cell. A number of these potent antiviral compounds and their related analogs have exhibited informative chemical structure-biological activity relationships (SAR). The goal of the Phase II proposal is to advance these compounds toward clinical development, to submit an application for an Investigational New Drug (IND) for the strongest candidate, and to identify at least one additional preclinical candidate as a potential back-up compound if needed. Lead compounds will be optimized by criteria of potency, toxicity, metabolism, and pharmacokinetics. Compounds that demonstrate acceptable traits will be evaluated for efficacy in animal models of Lassa fever. These experiments will be performed initially in guinea pigs, with efficacious compounds further tested in nonhuman primates. In addition, the mechanism of antiviral action will be explored both directly and by examination of prospective viral escape mutants. Replication-deficient retroviruses that incorporate a heterologous envelope protein such as the Lassa fever virus glycoprotein (viral pseudotypes) will be used to assess compound potency and mechanism of action; these experiments can be performed using biosafety level 2 (BSL-2) conditions. Results will be validated in BSL-4 facilities using authentic Lassa fever virus; animal studies using Lassa fever virus will also be conducted in BSL-4 facilities.