Arenavirus entry and it's inhibition

沙粒病毒的进入及其抑制

• 批准号: 7675664
• 负责人: Jack H Nunberg
• 金额: $ 32.17万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675664
• 关键词: Address; American Hemorrhagic Fever; Antiviral Agents; Arenavirus; Arenavirus Infections; Bioavailable; Categories; Cavia; Cell Culture Techniques; Cells; Chemicals; Cleaved cell; Clinical; Collaborations; Complex; Computing Methodologies; Development; Disease; Drug resistance; Endosomes; Family; Glycoproteins; Goals; Individual; Infection; Intervention; Junin virus; Knowledge; Lassa Fever; Lassa fever virus; Lead; Mediating; Membrane; Membrane Fusion; Membrane Fusion Activity; Methods; Modeling; Molecular; Molecular Virology; National Institute of Allergy and Infectious Disease; National Security; Old World Arenaviruses; Peptide Signal Sequences; Pharmaceutical Chemistry; Pharmaceutical Preparations; Population; Public Health; Relative (related person); Research Project Grants; Rodent; Role; Series; South American; Species Specificity; Structure-Activity Relationship; Technology; Therapeutic; Treatment Efficacy; Variant; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Work; animal rule; base; biodefense; design; effective therapy; inhibitor/antagonist; mortality; nonhuman primate; novel; pharmacophore; pre-clinical; prevent; prototype; receptor binding; small molecule; viral interferon regulatory factor

Arenaviruses are responsible for hemorrhagic fevers with high mortality. Effective therapies against Lassa fever virus (LASV) and Argentine hemorrhagic fever virus (Junin, JUNV) infections are urgently needed to address public health and national security concerns. Intervention strategies directed at the arenavirus envelope glycoprotein (GPC) provide a rational basis for the development of novel antiviral agents. We have recently demonstrated that an interaction between the ectodomains of the GPC fusion subunit (G2) and the unusual stable signal peptide (SSP) is essential for pH-dependent activation of GPCmediated membrane fusion. Interestingly, our preliminary results strongly suggest this interaction is targeted by small-molecule compounds (SIGA Technologies) that act to stabilize the pre-fusion GPC complex against low pH activation, thereby preventing virus entry. Importantly, a prototype inhibitor ST-193 has been shown to protect against lethal LASV infection in guinea pigs. We have established a collaboration with SIGA to capitalize on our knowledge of GPC and these promising lead compounds, in order to identify a broadspectrum arenavirus therapeutic for clinical development. The specific aims of this proposal are: 1. To identify and characterize molecular determinants of the SSP-G2 interface that are responsible for the antiviral activity of SIGA fusion inhibitors. We will examine the contributions of individual sidechains to membrane-fusion activity and its inhibition. We will explore the role of sequence variation in JUNV and LASV in imparting species specificity to these compounds. Drug-resistant isolates derived in cell culture will be used to identify sidechains important for antiviral activity. 2. To characterize structural features of SIGA inhibitors that contribute to their antiviral activity. We will investigate chemical derivatives of lead compounds to define structure-activity relationships that determine potency and breadth of inhibition. We will also capitalize on the structural diversity of four distinct chemical classes of SIGA inhibitors to model a common pharmacophore using computational methods. 3. To evaluate the therapeutic efficacy of selected inhibitors. Optimized, drug-like compounds will be used in guinea pig models of pre-symptomatic JUNV and LASV infection to determine therapeutic efficacy. These studies will be important in the selection of a compound for non-human primate studies in accordance with the FDA Two-Animal Rule for IND filing and clinical development. This work fits within the RMRCE IRF-Viral Therapeutics, and interacts with RP 3.4.

沙粒病毒是导致高死亡率的出血热的原因。有效的治疗方法， 拉沙热病毒（LASV）和阿根廷出血热病毒（朱宁，JUNV）感染， 需要解决公共卫生和国家安全问题。干预战略， 沙粒病毒囊膜糖蛋白（GPC）的研究为开发新型抗病毒药物提供了理论依据 剂.我们最近证明了GPC融合蛋白的胞外域之间的相互作用 亚基（G2）和不寻常的稳定信号肽（SSP）对于GPC介导的pH依赖性活化是必需的。 膜融合有趣的是，我们的初步结果强烈表明这种相互作用是有针对性的， 通过小分子化合物（SIGA Technologies），其作用是稳定熔融前GPC复合物， 低pH活化，从而防止病毒进入。重要的是，原型抑制剂ST-193已被证明是 保护豚鼠免受致命的LASV感染。我们与SIGA建立了合作关系， 利用我们对GPC和这些有前途的先导化合物的知识，以确定一个广谱的 用于临床开发的沙粒病毒治疗剂。该提案的具体目标是：1.到 确定和表征SSP-G2界面的分子决定因素，这些决定因素负责 SIGA融合抑制剂的抗病毒活性。我们将研究单个侧链对 膜融合活性及其抑制。我们将探讨序列变异在JUNV和LASV中的作用 赋予这些化合物物种特异性。细胞培养中产生的耐药分离株将 用于鉴定对抗病毒活性重要的侧链。2.表征SIGA的结构特征 抑制剂有助于其抗病毒活性。我们将研究铅的化学衍生物 化合物来定义结构-活性关系，从而决定抑制的效力和广度。我们将 还利用四种不同化学类别的SIGA抑制剂的结构多样性来模拟 共同药效团使用计算方法。3.目的：评价 选择抑制剂。优化的药物样化合物将用于症状前的豚鼠模型， JUNV和LASV感染，以确定治疗效果。这些研究将是重要的选择 根据FDA IND申报的双动物规则，非人灵长类动物研究的化合物 临床发展。这项工作符合RMRCE IRF-病毒治疗学，并与RP 3.4相互作用。