Antiviral Drugs for Lassa Fever Virus

拉沙热病毒的抗病毒药物

• 批准号: 7108724
• 负责人: SEAN M AMBERG
• 金额: $ 97.5万
• 依托单位: SIGA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108724
• 关键词: Lassa virus; lead; model; pharmacokinetics; toxicology

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.

描述（由申请人提供）：出血热病毒在全球范围内严重关注以及潜在的生物武器。特别是LASSA发烧病毒在西非每年都会感染数十万人，并且该地区在该地区以外的病原体出口，无论是故意还是无意间，对世界发达国家造成了严重的风险。 CDC和NIAID已将LASSA热病毒确定为优先病原体，表明对公共卫生的威胁最高。我们的生物化计划的目的是开发安全有效的药物，以预防和治疗由A类病毒引起的疾病。为此，筛选了一个较大的小分子化合物文库，以鉴定靶向必需LASSA表面糖蛋白的抑制剂，从而阻止病毒进入宿主细胞。这些有效的抗病毒化合物及其相关的类似物中的许多具有信息化学结构生物学活性关系（SAR）。第二阶段提案的目的是将这些化合物推向临床开发，向最强候选人提交研究新药（IND）的申请，并在需要时将至少一个额外的临床前候选者确定为潜在的备用化合物。铅化合物将通过效力，毒性，代谢和药代动力学的标准进行优化。表现出可接受性状的化合物将在LASSA热的动物模型中评估有效性。这些实验最初将在豚鼠中进行，并在非人类灵长类动物中进一步测试了有效的化合物。此外，将直接和检查前瞻性病毒逃生突变体探索抗病毒作用的机制。复制缺陷逆转录病毒融合了异源包膜蛋白，例如Lassa Fever病毒糖蛋白（病毒假型），以评估复合效力和作用机理；这些实验可以使用生物安全级别2（BSL-2）条件进行。结果将在BSL-4的设施中使用正宗的LASSA发烧病毒进行验证；使用LASSA热病毒的动物研究也将在BSL-4设施中进行。