A Novel Broad-spectrum Antiviral Agent

一种新型广谱抗病毒药物

• 批准号: 10323057
• 负责人: Jason W. Botten
• 金额: $ 29.07万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323057
• 关键词: 2019-nCoV; Address; Affinity; Americas; Animals; Antibodies; Antiviral Agents; Arenavirus; Binding; Biological Products; Bioterrorism; COVID-19; COVID-19 pandemic; Carbohydrates; Cells; Cessation of life; Clinical; Coagulation Factor Deficiency; Coronavirus; Data; Development; Development Plans; Disease; Disease Outbreaks; Dose; Ebola; Ebola virus; Economic Burden; Economics; Epidemic; Escape Mutant; FDA approved; Family; Fatality rate; Filovirus; Fright; Future; Generations; Genome; Glycoproteins; Goals; Golgi Apparatus; Hantavirus; Human; In Vitro; Incidence; Infant; Infection; Influenza; Influenza A virus; Junin virus; KAI1 gene; Lassa virus; Lead; Ligands; Logistics; Lymphocytic choriomeningitis virus; Mannose Binding Lectin; Maps; Marburgvirus; Microcephaly; Middle East Respiratory Syndrome; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mutation; National Institute of Allergy and Infectious Disease; Orphan; Orthomyxoviridae; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Phase; Pregnancy; Protein Deficiency; Proteins; RNA Viruses; Recombinants; Risk; SARS coronavirus; Safety; Severe Acute Respiratory Syndrome; Site; Structural Protein; Technology; Therapeutic; Time; Travel; Vaccines; Viral; Viral Genome; Viral Structural Proteins; Virion; Virus; Vulnerable Populations; ZIKA; Zika Virus; anterograde transport; base; combat; cost; economic cost; effective therapy; experience; experimental study; extracellular; human disease; immunogenicity; influenzavirus; innovation; microorganism; mortality; novel; pandemic disease; particle; pathogen; pathogenic virus; pharmacokinetics and pharmacodynamics; preclinical development; preclinical toxicity; priority pathogen; prophylactic; receptor; severe COVID-19; targeted agent; therapeutic target; vaccine access; virus envelope

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.

概括 一系列病毒流行病的加速出现和重新出现是这次疫情的一个致命特征。 21世纪。很少有有效的疗法可以对抗这些疾病，而且一般来说， 世界仍然没有做好应对未来疫情爆发的准备。最近一次埃博拉病毒的爆发导致 超过 11,000 人死亡，超过 20,000 名孤儿，经济成本超过 $32B（世界银行），并灌输 还有更多人有不同程度的恐惧。但埃博拉病毒并不是独一无二的。 2003年非典造成的全球经济损失 病毒约为 $40B (WHO)。 2017 年，由于以下原因，美洲境内出现了旅行和怀孕限制： 寨卡病毒及其与婴儿小头畸形发病率激增的高度相关性。当前，世界正 经历了危及生命的 COVID-19 (SAR2-CoV-2) 大流行带来的前所未有的困难， 已导致全球超过 150,000 人死亡，且尚无有效疗法或疫苗。 不幸的是，这既不是世界第一次也不是最后一次陷入这种困境，除非广泛采取行动。 一线药物可快速调配。这些疫情都是由RNA病毒引起的， 仍然是一个尚未解决的主要疾病类别。沙粒病毒（例如拉沙热病毒和胡宁病毒）、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） 有包膜的 RNA 病毒会导致严重且往往致命的人类疾病。尽管对全球造成影响和损失 人类生命，没有有效的治疗方案或 FDA 批准的疫苗来对抗这些疾病 毁灭性感染，因此它们被归类为 NIAID 优先病原体，并且也在选择范围内 潜在生物恐怖主义威胁的代理人名单。 该提案旨在通过开发广泛的产品来解决这一非常重要的、未满足的临床需求 抗病毒剂 (BSAA)，针对通常被多种病原体破坏的基本宿主蛋白 病毒家族，但对宿主来说不是必需的。特别是，我们建议针对人类 ER-高尔基体中间体 区室蛋白 53 kDa 蛋白 (ERGIC-53)，一种甘露糖特异性凝集素，充当细胞内凝集素 货物受体促进早期胞吐中选定的细胞糖蛋白配体的顺行运输 途径。我们已经证明，ERGIC-53 对于沙粒病毒、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相关 以及正粘病毒和汉坦病毒，ii) 运输到病毒出芽位点，并且 iii) 被纳入 病毒颗粒。在没有 ERGIC-53 的情况下，含有正常阵列和病毒数量的病毒颗粒 结构蛋白和基因组已形成，但不再具有传染性。具体来说，缺乏 ERGIC-53 的病毒粒子 它们附着于宿主细胞的能力有缺陷。我们已经在 ERGIC-53 中映射了最小域 是控制病毒粒子感染性所必需的，并且表明该区域的细胞外靶向有效中和 多种致病性RNA病毒的传染性。 在此，我们提出了针对 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 的强效抗病毒单克隆抗体将是 在治疗病毒爆发方面具有开创性。由于其广谱活性和预期的安全性 在靶点调节方面，ERGIC-53 靶向有潜力成为对抗许多 RNA 病毒的一线策略。