A Novel Broad-spectrum Antiviral Agent

总结 各种病毒性流行病的加速出现和重新出现一直是本世纪的一个致命特征， 21世纪世纪。有效的甚至是有效的治疗方法很少能用于对抗这些疾病，一般来说， 世界仍然没有做好应对未来疫情的准备。最近一次埃博拉病毒爆发导致 超过11，000人死亡，20，000多名孤儿，经济成本超过320亿美元（世界银行）， 不同程度的恐惧但埃博拉病毒并不是独一无二的; 2003年，SARS造成的全球经济损失 病毒约为400亿美元（世卫组织）。在2017年，由于美国的移民政策， 寨卡病毒及其与婴儿小头畸形发病率激增的高度相关性。目前，世界 经历了威胁生命的COVID-19（SAR 2-CoV-2）大流行带来的前所未有的困难， 已经导致全球超过15万人死亡，并且没有有效的治疗方法或疫苗。 不幸的是，这既不是第一次，也不是最后一次，世界预计将在这种困境，除非广泛的 可快速部署一线药物。这些爆发都是由RNA病毒引起的， 仍然是一个主要的未解决的疾病类别。沙粒病毒（例如拉沙热病毒和朱宁病毒），冠状病毒 （包括SARS-COV-1、SARS-CoV-2和MERS）和丝状病毒（例如埃博拉病毒和马尔堡病毒）是 有包膜的RNA病毒，可引起严重且往往致命的人类疾病。尽管全球性的影响和损失， 人的生命，没有有效的治疗选择或FDA批准的疫苗可用于对抗这些 毁灭性的感染，因此它们被归类为NIAID优先病原体， 潜在生物恐怖威胁的特工名单 该提案旨在通过开发一种广泛的 一种抗病毒剂（BSAA），靶向一种基本的宿主蛋白，该蛋白通常被多种病原体破坏 病毒家族，但对宿主不是必需的。特别是，我们建议靶向人类ER-高尔基体中间体 隔室蛋白53 kDa蛋白（ERGIC-53），一种甘露糖特异性凝集素，作为细胞内 货物受体，以促进选择的细胞糖蛋白配体在早期胞外 通路我们已经证明，ERGIC-53是沙粒病毒、冠状病毒、 和丝状病毒。特别地，ERGIC-53 i）与这些病毒编码的包膜糖蛋白结合 以及正粘病毒和汉坦病毒，ii）向病毒出芽位点的运输，和iii）并入 病毒颗粒在不存在ERGIC-53的情况下，含有正常阵列和病毒量的病毒颗粒可被检测到。 结构蛋白和基因组形成，但不再具有传染性。具体地说，缺乏ERGIC-53的病毒体 在附着于宿主细胞的能力上有缺陷。我们已经映射了ERGIC-53中的最小域， 是控制病毒体感染性所必需的，并显示该区域的细胞外靶向有效地中和了 多种病原性RNA病毒的感染性。 在此，我们提出了靶向ERGIC-53的强有力的科学依据和概念数据证明， ERGIC-53的细胞外靶向是有效的抗病毒靶点。我们的发展计划包括 与Lake Pharma合作，Lake Pharma是一家在抗体生成技术方面拥有良好记录的公司。 成功开发针对ERGIC-53的有效抗病毒单克隆抗体将是 在病毒爆发的治疗方面具有开创性。由于其广谱活性和预期的安全性 ERGIC-53靶向具有成为对抗许多RNA病毒的一线策略的潜力。

Summary Accelerating emergence and re-emergence of a wide array of viral epidemics has been a deadly feature of the 21st century. Potent or even effective therapies are rarely available to combat these diseases, and in general, the world remains unprepared to manage future outbreaks. The most recent outbreak of the Ebola virus resulted in over 11,000 fatalities, more than 20,000 orphans, and economic costs of >$32B (Worldbank), and instilled varying levels of fear in many more. But Ebola is not unique; in 2003 the global economic loss from the SARS virus was ~$40B (WHO). In 2017, there were travel and pregnancy restrictions within the Americas due to the Zika virus and its high correlation with the surge in the incidences of infant microcephaly. Currently, the world is experiencing unprecedented hardship from the life-threatening COVID-19 (SAR2-CoV-2) pandemic, which has already resulted in over 150,000 deaths worldwide, and for which there is no effective therapy or vaccine. Unfortunately, this is neither the first nor the last time the world is expected to be in this plight, unless a broadly acting first-line drug is available for rapid deployment. These outbreaks all resulted from RNA viruses, which remain a major unaddressed disease class. Arenaviruses (e.g. Lassa fever virus and Junin virus), coronaviruses (including SARS-COV-1, SARS-CoV-2, and MERS), and filoviruses (e.g. Ebola and Marburg viruses) are enveloped RNA viruses that cause severe and often fatal human diseases. Despite the global impact and toll on human lives, there are no effective treatment options or FDA-approved vaccines available to combat these devastating infections and they are accordingly classified as NIAID Priority Pathogens and are also on the select agent list of potential bioterrorism threats. This proposal seeks to address this highly significant, unmet clinical need by developing a broad spectrum antiviral agent (BSAA) that targets a fundamental host protein that is commonly subverted by multiple pathogenic virus families but is not essential for the host. In particular, we propose to target the human ER-Golgi intermediate compartment protein 53 kDa protein (ERGIC-53), a mannose-specific lectin that functions as an intracellular cargo receptor to facilitate the anterograde transport of selected cellular glycoprotein ligands in the early exocytic pathway. We have shown that ERGIC-53 is critically required for the propagation of arenaviruses, coronaviruses, and filoviruses. In particular, ERGIC-53 i) associates with the envelope glycoproteins encoded by these viruses as well as orthomyxoviruses and hantaviruses, ii) traffics to sites of virus budding, and iii) is incorporated into viral particles. In the absence of ERGIC-53, viral particles containing the normal array and quantity of viral structural proteins and genome are formed but are no longer infectious. Specifically, virions lacking ERGIC-53 are defective in their ability to attach to host cells. We have mapped the minimal domain within ERGIC-53 that is required for controlling virion infectivity and shown that extracellular targeting of this region potently neutralizes the infectivity of multiple pathogenic RNA viruses. Herein, we have presented strong scientific rationale for targeting ERGIC-53 and proof of concept data that extracellular targeting of ERGIC-53 is an effective antiviral target. Our development plan includes collaborating with Lake Pharma, a company with a proven track record in antibody generation technology. The successful development of potent antiviral monoclonal antibodies targeting ERGIC-53, would be groundbreaking in the treatment of viral outbreaks. Due to its broad spectrum activity and the expected safety of target modulation, ERGIC-53 targeting has the potential to be a first-line strategy against many RNA viruses.