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

• 批准号: 9204792
• 负责人: Jeanne Sisk
• 金额: $ 5.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/9204792
• 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; Coronaviridae; Coronavirus; Coronavirus Infections; Country; Dasatinib; Data; Disease; Disease Outbreaks; Disease model; Drug effect disorder; Drug usage; Effectiveness; Endocytosis; Endosomes; Enteral; FDA approved; Family; Flow Cytometry; Future; Genetic Transcription; Goals; Health Personnel; Health Services Accessibility; Human; Imatinib; Infection; Inflammatory Response; International; Life Cycle Stages; Lung diseases; Lysosomes; Mediating; Membrane; Middle East; Middle East Respiratory Syndrome Coronavirus; Molecular Mechanisms of Action; Monitor; Mus; Neuraxis; Paper; Pathogenicity; 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; Virus; Virus Replication; Work; Writing; biosafety level 3 facility; cancer type; effective therapy; efficacy study; experimental study; in vivo; kinase inhibitor; late endosome; meetings; mouse model; novel; permissiveness; prevent; protein expression; public health relevance; respiratory; respiratory virus; skills; tool; trafficking; viral RNA

 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（由申请人提供）：冠状病毒引起呼吸、肠道和中枢神经系统疾病。直到最近，这些病毒还被认为会引起轻微的症状，例如普通感冒。 2003 年由 SARS 冠状病毒 (SARS-CoV) 引起的严重急性呼吸系统综合症 (SARS) 爆发后，这种看法发生了变化。该病毒在全球迅速传播，导致 32 个国家超过 8000 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）。该病毒目前已感染 21 个国家 800 多人，导致 300 多人死亡。这些疫情的爆发表明，冠状病毒是对公众健康的主要威胁，迄今为止，还没有针对 SARS-CoV 或 MERS-CoV 的有效疗法。这项研究的主要目标是确定 FDA 批准的可重新用于治疗冠状病毒引起的感染的药物，并确定其预防疾病的细胞和分子作用机制。 Abl 激酶抑制剂可抑制 SARS-CoV 和 MERS-CoV 的感染。初步数据表明，Abl 激酶抑制剂可在病毒生命周期的早期阶段阻断复制。该研究的目标 1 将确定 Abl 激酶抑制剂是否以及如何阻止冠状病毒通过内体/溶酶体途径运输，以及组织蛋白酶 L 等关键内体融合蛋白是否受到 ABL 激酶抑制剂的影响。目标 2 将确定 Abl 激酶抑制剂是否可以预防小鼠体内冠状病毒的复制和肺部病理学。体内抑制研究将利用已建立的致命 SARS-CoV 小鼠模型和新开发的 MERS-CoV 小鼠模型，该模型使用新型人类 DPP4 转基因小鼠。鉴于过去十年中出现了两种不同的冠状病毒，迫切需要找到有效的方法 SARS-CoV 和 MERS-CoV 感染的治疗。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。