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

• 批准号: 9197959
• 负责人: Gary R Whittaker
• 金额: $ 23.49万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9197959
• 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; Paramyxoviridae; 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; Treatment Efficacy; 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; virus envelope

 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（由申请人提供）：许多包膜病毒的融合蛋白通过蛋白水解引发步骤被激活。引发事件利用宿主细胞蛋白酶在包膜（融合）蛋白中进行特异性切割，通常在紧邻包膜蛋白的位置。融合肽的暴露是病毒进入过程的关键部分，没有蛋白水解引发，病毒感染就无法启动。宿主细胞蛋白酶是许多疾病的重要药物靶点，但参与病毒进入的宿主细胞蛋白酶的靶向性却很少受到关注。 我们提出高度特异性的抑制剂，其对其天然蛋白酶具有高亲和力。 利用这种天然抑制剂作为流感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，在人类病例中，引发不是通过单一蛋白酶发生的，而是通过亚蛋白酶发生的。因此，具有某种程度广泛特异性的单一天然（或修饰天然）抑制剂可能是一种可行的抗病毒治疗方法，因为多个病毒家族可能具有相同或重叠的激活作用。作为治疗流行性和大流行性流感的主要疗法，单一抑制剂也可能对不同家族的病毒亚组具有活性。以及包括副粘病毒在内的其他包膜病毒。我们该项目的重点是甲型和乙型流感病毒，以及人类偏肺病毒和人类副流感病毒1。我们建议描述我们的主要候选病毒。抑制剂，无论是在体外还是在细胞培养物中，包括原代呼吸道细胞，并开​​发具有改进效力的工程衍生物。鉴于许多病毒是由宿主细胞蛋白酶激活的，我们认为这一策略是谨慎的，我们的最终目标是。开发一种可用于治疗多种传染源的系统。