Development of novel protease inhibitors for influenza and paramyxoviruses

开发针对流感和副粘病毒的新型蛋白酶抑制剂

基本信息

批准号：
9035762
负责人：
Gary R Whittaker
金额：
$ 22.19万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9035762
关键词：
Affinity Attention Biochemical Biological Assay Cell Culture Techniques Cells Cellular biology Chimeric Proteins Development Disease Drug Targeting Effectiveness Engineering Epidemic Epithelial Cells Event Family Goals Human Human Metapneumovirus In Vitro Infectious Agent Influenza Influenza A virus Influenza B Virus Influenza Hemagglutinin Influenza Therapeutic Laboratories Lead Modeling Para-Influenza Virus Type 1 Paramyxovirus Peptide Hydrolases Peptides Pharmaceutical Preparations Process Protease Inhibitor Protein Inhibition Proteins Public Health Regulation Respiratory System Respiratory tract structure ST14 gene Serine Protease Serine Proteinase Inhibitors Specificity System Therapeutic Therapeutic Index Therapeutic Uses Tissues Trypsin Viral Virus Virus Diseases base cell type improved influenzavirus inhibitor/antagonist interest man novel novel therapeutics pandemic influenza pathogen preference public health relevance respiratory respiratory virus seasonal influenza targeted treatment therapeutic development therapeutic target trypsin-like serine protease virology

项目摘要

DESCRIPTION (provided by applicant): The fusion proteins of many enveloped viruses are activated by a proteolytic priming step. The priming event utilizes a host cell protease to make a specific cleavage in the envelope (fusion) protein, often in the immediate vicinity of the fusion peptide. Exposure of the fusion peptide is a critical part of the virus entry process, and without proteolytic priming, virus infection cannot be initiated. While proteases are important drug targets for many diseases, the targeting of host cell proteases involved in virus entry has received little attention. Host cell proteases are usually under tight regulation, and the host has evolved highly specific inhibitors, which have high affinity for their natural protease. We propose to take advantage of such natural inhibitors as a host-targeted therapeutic approach for influenza and other respiratory viruses. In the case of viral infection, it is apparent that in man cases priming is not occurring via a single protease, but rather via a sub-set of related proteases expressed in a given tissue. Thus a single natural (or modified-natural) inhibitor with some degree of broad specificity is likely to be a viable anti-viral therapeutic. As several virus families likely share the same or overlapping activating proteases, a single inhibitor is also likey to be active against a sub-set of viruses in distinct families. We have recently developed a kunitz-type protease inhibitor (SPINT2 or HAI-2) as a lead therapeutic for treatment of epidemic and pandemic influenza, as well as other enveloped viruses including paramyxoviruses. Our focus in the project will be influenza A and B viruses, as well as human metapneumovirus and human parainfluenza virus 1. We propose to characterize our lead candidate inhibitor, both in vitro and in cell culture, including primary respiratory tract cells, and to develop engineered derivates with improved potency. Given that many viruses are activated by host cell proteases, we feel this strategy is a prudent one, with our eventual goal being to develop a system that can be used to treat multiple infectious agents.

描述（由适用提供）：许多包膜病毒的融合蛋白通过蛋白水解启动步骤激活。启动事件利用宿主细胞蛋白在包膜（融合）蛋白中进行特定的裂解，通常是在融合肽的附近。融合肽的暴露是病毒进入过程的关键部分，如果没有蛋白水解启动，就无法引发病毒感染。尽管蛋白酶是许多疾病的重要药物靶标，但涉及进入病毒的宿主细胞蛋白酶的靶向很少受到关注。宿主细胞蛋白酶通常受到严格调节，宿主具有进化出高度特异性的抑制剂，它们对其天然蛋白酶具有很高的亲和力。我们建议利用这种天然抑制剂作为影响力和其他呼吸道病毒的宿主靶向治疗方法。在病毒感染的情况下，很明显，在人体病例中，启动不是通过单个蛋白酶发生的，而是通过在给定组织中表达的相关蛋白的子集发生。具有一定程度特异性的单一天然（或修饰自然）抑制剂可能是一种可行的抗病毒疗法。由于几个病毒家族可能具有相同或重叠的活化蛋白，因此单一抑制剂也喜欢在不同家族中对一组病毒的次数活跃。我们最近开发了一种kunitz型蛋白抑制剂（SPINT2或HAI-2），作为治疗流行病和大流行影响的铅疗法，以及其他包膜病毒，包括参氧病毒。我们对该项目的重点将受到影响，以及人类的丙型病毒和人类副病毒病毒1。我们建议在体外和细胞培养中表征我们的铅候选抑制剂，包括初级呼吸道细胞，以及通过改善的效力增强工程衍生物。鉴于许多病毒被宿主细胞蛋白酶激活，我们认为这种策略是一种谨慎的策略，我们的最终目标是开发可用于治疗多种感染剂的系统。