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Repurposing of ABL kinase inhibitors for treatment of Coronavirus infections

重新利用 ABL 激酶抑制剂治疗冠状病毒感染

基本信息

批准号：
9258595
负责人：
Jeanne Sisk
金额：
$ 5.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258595
关键词：
Affect Biological Assay Bypass Cathepsin L Cell Culture Techniques Cells Cessation of life Chimeric Proteins Clathrin Cleaved cell Clinical Trials Common Cold Communicable Diseases Confocal Microscopy Coronavirus Coronavirus Infections Country Dasatinib Data Disease Disease Outbreaks Drug effect disorder Drug usage Effectiveness Endocytosis Endosomes Enteral FDA approved Family Flow Cytometry Future Goals Health Health Personnel Health Services Accessibility Human Imatinib Infection Inflammatory Response International Life Life Cycle Stages Lung diseases Lysosomes Mediating Membrane Middle East Middle East Respiratory Syndrome Coronavirus Molecular Mechanisms of Action Monitor Mus Neuraxis Paper Pathology Pathway interactions Peer Review Peptide Hydrolases Perception Pharmaceutical Preparations Preparation Proteins Public Health Pulmonary Pathology Research Severe Acute Respiratory Syndrome Surface Symptoms Testing Training Transgenic Mice Viral Viral Pathogenesis Viral Proteins Virus Virus Replication Work Writing biosafety level 3 facility cancer type effective therapy in vivo kinase inhibitor late endosome meetings mouse model novel prevent protein expression research study respiratory respiratory virus skills tool trafficking viral RNA

项目摘要

DESCRIPTION (provided by applicant): Coronaviruses cause disease of the respiratory, enteric and central nervous systems. Until recently, these viruses were thought to cause mild symptoms, such as the common cold. This perception changed after the severe acute respiratory syndrome (SARS) outbreak in 2003, caused by the SARS-Coronavirus (SARS-CoV). The virus spread rapidly around the world causing over 8000 infections in 32 countries leading to over 800 deaths. In 2012, another highly pathogenic human coronavirus emerged from the Middle East called the Middle East respiratory syndrome-Coronoavirus (MERS- CoV). This virus currently has infected over 800 people, resulting in over 300 deaths in 21 countries. These outbreaks demonstrate that Coronaviruses are a major threat to public health, and to date, there are no effective therapies to target either SARS-CoV or MERS-CoV. The broad objective of this study is to identify FDA-approved drugs that may be repurposed to treat infections caused by Coronaviruses, as well as to determine their cellular and molecular mechanisms of action in preventing disease. Abl kinase inhibitors inhibit infection by both SARS-CoV and MERS-CoV. Preliminary data demonstrates that Abl kinase inhibitors block replication at early steps in the virus life cycle. Aim 1 of the study will determine whether and how Abl kinase inhibitors prevent Coronavirus trafficking through the endosome/lysosome pathway and whether key endosomal fusion proteins, like Cathepsin L, are affected by ABL kinase inhibitors. Aim 2 will identify whether Abl kinase inhibitors prevent Coronavirus replication and lung pathology in mice. The in vivo inhibition studies will utilize both an established lethal SARS-CoV mouse model and a newly developed MERS-CoV mouse model using a novel human DPP4 transgenic mice. Given that two distinct Coronaviruses have emerged in the last decade, it is imperative to find effective treatments for SARS-CoV and MERS-CoV infection. These tools will allow healthcare providers to access treatments and prevent future disease outbreaks.

描述（由申请方提供）：冠状病毒引起呼吸系统、肠道和中枢神经系统疾病。直到最近，这些病毒被认为会引起轻微的症状，如普通感冒。这种看法在2003年由SARS冠状病毒（SARS-CoV）引起的严重急性呼吸道综合征（SARS）爆发后发生了变化。该病毒在世界各地迅速蔓延，在32个国家造成8000多人感染，导致800多人死亡。2012年，另一种高致病性人类冠状病毒从中东出现，称为中东呼吸综合征-冠状病毒（MERS-CoV）。这种病毒目前已感染800多人，在21个国家造成300多人死亡。这些爆发表明，冠状病毒是对公共卫生的主要威胁，迄今为止，还没有针对SARS-CoV或MERS-CoV的有效疗法。这项研究的主要目的是确定FDA批准的药物，这些药物可能被重新用于治疗冠状病毒引起的感染，并确定它们在预防疾病方面的细胞和分子作用机制。Abl激酶抑制剂抑制SARS-CoV和MERS-CoV的感染。初步数据表明，Abl激酶抑制剂在病毒生命周期的早期阶段阻断复制。该研究的目的1将确定Abl激酶抑制剂是否以及如何防止冠状病毒通过内体/溶酶体途径运输，以及关键的内体融合蛋白（如组织蛋白酶L）是否受到ABL激酶抑制剂的影响。目的2将确定Abl激酶抑制剂是否预防冠状病毒复制和小鼠肺病理学。体内抑制研究将利用已建立的致死SARS-CoV小鼠模型和新开发的MERS-CoV小鼠模型（使用新型人DPP 4转基因小鼠）。鉴于在过去十年中出现了两种不同的冠状病毒，治疗SARS-CoV和MERS-CoV感染。这些工具将使医疗保健提供者能够获得治疗并预防未来的疾病爆发。