Peptide inhibitors of coronavirus entry

冠状病毒进入的肽抑制剂

基本信息

批准号：
8715498
负责人：
Samuel Earl Hopkins
金额：
$ 22.5万
依托单位：
AUTOIMMUNE TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715498
关键词：
Acute Disease Algorithms Animals Antiviral Agents Antiviral Therapy Autoimmune Process Binding Bioterrorism Case Fatality Rates Categories Cell membrane Cells Centers for Disease Control and Prevention (U.S.)Clinical Clinical Research Common Cold Computing Methodologies Coronavirus Coronavirus Infections Data Dengue Development Disease Disease Outbreaks Dose Epidemic Exposure to Family Ferrets Frequencies Functional disorder Future Human Human Coronavirus 229E Human Coronavirus OC43 Immune response In Vitro Infection Influenza Influenza A virus Influenza B virus Laboratories Lead Lipid Bilayers Medical Membrane Methods Middle East Mink Modeling National Institute of Allergy and Infectious Disease National Security Patients Peptides Persons Pharmaceutical Preparations Phase Plaque Assay Population Process Protein S Protein Sequence Analysis Proteins RNA RNA Viruses Reproducibility Research Respiratory Tract Infections Safety Severe Acute Respiratory Syndrome Severe Adverse Event Surface Syndrome System Technology Testing Therapeutic Therapeutic Uses Toxic effect Vaccines Validation Viral Viral Fusion Proteins Virus Work animal model development anti-influenza base design drug candidate drug development flu transmission human coronavirus human disease in vivo in vivo Model inhibitor/antagonist member mortality novel pathogen prevent programs public health relevance research clinical testing respiratory screening transmission process vaccine development virus development

项目摘要

DESCRIPTION (provided by applicant): The broad long-term objectives of the proposed work are to develop effective medical countermeasures to be used for the treatment of viral infectious disease caused by exposure to human coronaviruses. The work will focus on the discovery and development of peptide-based therapeutics for the treatment of persons infected with the newly identified Middle Eastern Respiratory Syndrome coronavirus (MERS CoV) with potentially wider utility of these therapeutics for use in the treatment of infections caused by the broad family of human coronaviruses. Our preliminary data indicate that short peptides which are derived from sequences representing novel functional domains within the loop region of the Spike protein of the SARS coronavirus are potent inhibitors of both SARS and MERS infection in vitro. We propose to design peptide drug candidates for the treatment of MERS CoV infection by using a combined approach of empiric antiviral screening together with computational methods as a means to identify peptides that interact with lipid bilayer membranes. Research in our laboratories indicates that these peptides exert potent antiviral activity by inhibiting fusion of he viral envelop to the host cell membrane. The specific aims of the proposed work are three-fold and include: 1.) Using well-established methods to evaluate the in vitro efficacy of peptides against all members of the broad family of human coronaviruses; 2.) Enhancing the safety, throughput and reproducibility of our antiviral screening methods by developing a pseudoparticle system for human coronaviruses; 3.) Development and validation of the mink as an in vivo model for evaluating the pathophysiology of MERS CoV infection and for testing the in vivo efficacy of lead peptides discovered in our screening program for activity against a valid model of MERS CoV infection. Successful completion of the specific aims will establish a robust discovery platform for the rapid identification of novel antiviral agents against emerging pathogens. The development of an animal model will be an essential step in order to support the introduction of these compounds into clinical testing as potential human therapeutics.

描述（由申请人提供）：拟议工作的广泛长期目标是开发有效的医学对策，用于治疗由人类冠状病毒导致的病毒传染病。这项工作将集中于基于肽的治疗剂的发现和开发，用于治疗新近鉴定的中东呼吸道综合征冠状病毒（MERS COV），这些治疗可能会在这些疗法中使用这些疗法的效用，以用于治疗由人类冠状病毒宽性家族引起的感染引起的感染。我们的初步数据表明，从代表SARS冠状病毒的尖峰蛋白的环路区域内代表新功能结构域的序列得出的短肽是体外SARS和MERS感染的有效抑制剂。我们建议通过使用经验性抗病毒筛查的组合方法与计算方法一起设计肽药物候选物来治疗MERS COV感染，以鉴定与脂质双层膜相互作用的肽。在我们的实验室中的研究表明，这些肽通过抑制HE病毒包膜与宿主细胞膜的融合来发挥有效的抗病毒活性。拟议工作的具体目的是三倍，其中包括：1。）使用良好的方法评估肽对人类冠状病毒的所有成员的体外疗效； 2.）通过开发用于人类冠状病毒的假颗粒系统，增强我们抗病毒筛查方法的安全性，吞吐量和可重复性； 3.）貂的开发和验证是评估MERS COV感染的病理生理学的体内模型，并测试了在我们的筛查计划中发现的铅肽的体内效果，以针对MERS COV感染的有效模型的活动模型。成功完成特定目标将建立一个强大的发现平台，以快速识别针对新兴病原体的新型抗病毒药。动物模型的发展将是支持将这些化合物引入临床测试作为潜在人类疗法的必不可少的一步。