A Novel Broad-spectrum Antiviral Agent

摘要 加速出现和重新出现广泛的病毒流行病一直是 21世纪。有效甚至有效的治疗方法很少用来对抗这些疾病，通常情况下， 世界仍未做好应对未来疫情的准备。最近一次埃博拉病毒的爆发导致 在超过11,000人死亡，20,000多名孤儿，以及320亿美元的经济成本(世界银行)，并灌输 更多的人有不同程度的恐惧。但埃博拉并不是独一无二的；2003年，SARS造成的全球经济损失 病毒约为400亿美元(世卫组织)。2017年，由于以下原因，美洲境内有旅行和怀孕限制 寨卡病毒及其与婴儿小头畸形症发病率激增的高度相关性。目前，世界正在 经历了危及生命的新冠肺炎(SARS-CoV-2)大流行带来的前所未有的困难 已经导致全世界150,000多人死亡，而且没有有效的治疗方法或疫苗。 不幸的是，这既不是世界第一次也不是最后一次预计会陷入这种困境，除非广泛的 代理一线药物可用于快速部署。这些疫情都是由RNA病毒引起的，它 仍然是一个主要的未解决的疾病类别。阿拉伯病毒(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)，以及丝状病毒(例如埃博拉和马尔堡病毒) 被包膜的RNA病毒，会导致严重的、通常是致命的人类疾病。尽管对全球造成了影响和损失 人类的生命，没有有效的治疗选择或FDA批准的疫苗来对抗这些 破坏性感染，因此它们被归类为NIAID优先病原体，也在精选名单上 潜在生物恐怖主义威胁的特工名单。 这项建议寻求通过开发广泛的频谱来解决这一高度重要的、未得到满足的临床需求 抗病毒剂(BSAA)，针对的是一种基本的宿主蛋白，该蛋白通常被多种致病因子破坏 病毒家族，但对宿主来说不是必需的。特别是，我们建议以人类ER-Golgi中间体为目标 间隔蛋白53 kDa蛋白(ERGIC-53)，一种甘露糖特异的凝集素，其功能是细胞内 Cargo受体在早期胞外促进选定细胞糖蛋白配体的顺行转运 路径。我们已经证明ERGIC-53对于阿拉伯病毒、冠状病毒、 和丝状病毒。特别是，ERGIC-53(I)与这些病毒编码的包膜糖蛋白有关 以及正粘病毒和汉坦病毒，ii)到病毒萌发地点的流量，以及iii)合并到 病毒颗粒。在没有ERGIC-53的情况下，含有正常排列和数量的病毒颗粒 结构蛋白和基因组已经形成，但不再具有传染性。具体地说，缺乏ERGIC-53的病毒粒子 它们附着在宿主细胞上的能力有缺陷。我们已经映射了ERGIC-53中的最小结构域 是控制病毒粒子感染性所必需的，并表明该区域的细胞外靶向有效地中和了 多种致病核糖核酸病毒的传染性。 在此，我们提出了以ERGIC-53为目标的强有力的科学依据和概念证明数据 ERGIC-53的细胞外靶向是一个有效的抗病毒靶点。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公认记录的公司。 针对ERGIC-53的有效抗病毒单抗的成功开发将是 在治疗病毒暴发方面具有开创性。由于它的广谱活性和预期的安全性 在靶向调控中，ERGIC-53靶向有可能成为对抗许多RNA病毒的一线策略。

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.