Repurposing of ABL kinase inhibitors for treatment of Coronavirus infections

 描述(申请人提供)：冠状病毒引起呼吸道、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，比如普通感冒。在2003年由SARS冠状病毒(SARS-CoV)引起的严重急性呼吸综合征(SARS)暴发后，这种看法发生了变化。该病毒在世界各地迅速传播，在32个国家造成8000多人感染，导致800多人死亡。2012年，另一种来自中东的高致病性人类冠状病毒出现，称为中东呼吸综合征-冠状病毒(MERS-CoV)。该病毒目前已感染800多人，导致21个国家300多人死亡。这些疫情表明，冠状病毒是对公众健康的主要威胁，到目前为止，还没有针对SARS-CoV或MERS-CoV的有效疗法。这项研究的广泛目标是确定FDA批准的可用于治疗冠状病毒感染的药物，并确定它们在预防疾病中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激酶抑制剂在病毒生命周期的早期阶段阻止复制。研究的目的1将确定abl激酶抑制剂是否以及如何通过内体/溶酶体途径阻止冠状病毒的转运，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激酶抑制剂是否能防止小鼠的冠状病毒复制和肺部病理。体内抑制研究将利用已建立的致死性SARS-CoV小鼠模型和新开发的MERS-CoV小鼠模型，该模型使用一种新的人类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，找到有效的方法是当务之急。 SARS冠状病毒和MERS冠状病毒感染的治疗。这些工具将使医疗保健提供者能够获得治疗并防止未来的疾病爆发。

 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.