Arenavirus entry and it's inhibition

ARENA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(JUNV)感染紧急 需要解决公共卫生和国家安全方面的关切。针对老年人的干预策略 阿拉伯病毒包膜糖蛋白(GPC)为开发新型抗病毒药物提供了合理的依据 探员们。我们最近已经证明了GPC融合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)是pH依赖的GPC介导的激活所必需的 膜融合。有趣的是，我们的初步结果强烈表明这种互动是有针对性的 通过小分子化合物(SIGA技术)稳定融合前的GPC复合体 低pH值激活，从而防止病毒入侵。重要的是，已经展示了一种原型抑制剂ST-193 以保护豚鼠免受致死性LASV感染。我们与SIGA建立了合作关系，以 利用我们对GPC和这些有希望的先导化合物的知识，以确定广谱 阿雷诺病毒治疗用于临床开发。这项建议的具体目的是：1. 识别和表征SSP-G2界面的分子决定因素，这些分子决定了 SIGA融合抑制剂的抗病毒活性。我们将检查个别侧链对 膜融合活性及其抑制。我们将探索序列变异在JUNV和LASV中的作用 赋予这些化合物物种专一性。在细胞培养中产生的耐药分离株将 用于识别对抗病毒活性重要的侧链。2.表征SIGA的结构特征 有助于其抗病毒活性的抑制剂。我们将研究铅的化学衍生品 化合物，以确定结构-活性关系，确定抑制的效力和广度。我们会 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 使用计算方法的普通药效基团。3.评价银杏叶提取物的治疗效果 选定的抑制剂。优化的类药物化合物将用于有症状前期的豚鼠模型 判断JUNV和LASV感染的疗效。这些研究将在遴选中发挥重要作用 用于非人类灵长类研究的化合物符合FDA关于IND备案的两动物规则 和临床发展。这项工作符合RMRCE IRF-病毒疗法，并与RP 3.4相互作用。

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.