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.