A Novel Broad-spectrum Antiviral Agent

一种新型广谱抗病毒药物

基本信息

批准号：
10156116
负责人：
Jason W. Botten
金额：
$ 29.99万
依托单位：
CELDARA MEDICAL, LLC
依托单位国家：
美国
项目类别：
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/10156116
关键词：
2019-nCoV Address Affinity Americas Animals Antibodies Antiviral Agents Arenavirus Binding Biological 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 Structure 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

项目摘要

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.

概括广泛的病毒流行病的加速出现和重新出现一直是致命的特征 21世纪。有效甚至有效的疗法很少能与这些疾病作斗争，总的来说世界仍然没有准备好管理未来的爆发。埃博拉病毒的最新暴发导致超过11,000人死亡，超过20,000个孤儿，经济成本> 32B美元（Worldbank）和灌输更多的恐惧程度不同。但是埃博拉病毒不是独一无二的。 2003年，SARS全球经济损失病毒约为$ 40B（WHO）。 2017年，由于 Zika病毒及其与婴儿小头畸形发病率激增的高相关性。目前，世界是从威胁生命的Covid-19（SAR2-COV-2）大流行中遇到前所未有的艰辛在全球范围内已经导致超过15万人死亡，并且没有有效的治疗或疫苗。不幸的是，这既不是第一次也不是世界上一次期望世界陷入困境，除非广泛代理一线药物可用于快速部署。这些暴发均由RNA病毒引起仍然是主要的未解决的疾病类别。体育症病毒（例如Lassa Fever病毒和Junin病毒），冠状病毒（包括SARS-COV-1，SARS-COV-2和MERS）以及丝状病毒（例如埃博拉病毒和马尔堡病毒）是包裹的RNA病毒引起严重且经常致命的人类疾病。尽管全球影响和损失人类的生活，没有有效的治疗选择或FDA批准的疫苗可与这些疫苗作斗争毁灭性的感染，因此被归类为NIAID优先病原体，也在选择中潜在生物恐怖主义威胁的代理清单。该建议旨在通过开发广泛的范围来满足这种高度重要，未满足的临床需求抗病毒剂（BSAA）靶向基本宿主蛋白，通常被多种致病性颠覆病毒家庭，但对宿主并不重要。特别是，我们建议针对人类ER-Golgi中间体室蛋白53 kDa蛋白（ERGIC-53），一种甘露糖特异性凝集素，可作为细胞内的凝集素货物受体促进早期外囊肿中选定的细胞糖蛋白配体的顺行转运路径。我们已经证明，ERGIC-53对于竞技病毒，冠状病毒，冠状病毒的传播至关重要。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联以及原病毒和汉坦病毒，ii）流动于病毒芽的部位，iii）纳入病毒颗粒。在没有ERGIC-53的情况下，含有正常阵列和数量病毒的病毒颗粒结构蛋白质和基因组形成，但不再具有感染性。具体而言，缺乏ERGIC-53的病毒体它们附着在宿主细胞上的能力有缺陷。我们已经绘制了Ergic-53中的最小域控制病毒体感染性需要，表明该区域的细胞外靶向有效中和多种致病性RNA病毒的感染性。在此，我们提出了针对ERGIC-53和概念数据证明的强大科学原理 ERGIC-53的细胞外靶向是有效的抗病毒靶标。我们的发展计划包括与Lake Pharma合作，该公司在抗体生成技术方面拥有良好的记录。靶向ERGIC-53的有效抗病毒单克隆抗体的成功开发将是在治疗病毒爆发方面的开创性。由于其广泛的活动和预期安全性在目标调节中，ERGIC-53靶向可能是针对许多RNA病毒的一线策略。