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Targeting Coronavirus through Nucleocapsid Phosphorylation

通过核衣壳磷酸化靶向冠状病毒

基本信息

批准号：
10239590
负责人：
PETER S KLEIN
金额：
$ 44.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-14 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239590
关键词：
2019-nCoV Antiviral Agents Arginine Attenuated Binding Biology COVID-19 COVID-19 testing COVID-19 treatment Cell Culture Techniques Cells Clinical Clinical Trials Collaborations Coronavirus Coronavirus Infections Coronavirus nucleocapsid protein Data Disease Disease Outbreaks Drug Targeting Epidemic Epithelial Cells Future Genetic Transcription Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Human Impairment Infection Institutes Knock-out Lead Lithium Lung Modeling Mutation Nucleocapsid Nucleocapsid Proteins Pathogenicity Patients Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Protein Inhibition Protein Kinase Proteins RNA replication Reporting Research Risk SARS coronavirus Serine Severe Acute Respiratory Syndrome Signal Transduction Site Testing Therapeutic Viral Virion Virus Replication alveolar epithelium clinical efficacy efficacy testing experimental study genomic RNA inhibitor/antagonist kinase inhibitor knock-down loss of function protective effect

项目摘要

Summary Coronaviruses express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV (responsible for SARS) by glycogen synthase kinase 3 (GSK- 3) is required for its function. GSK-3 inhibition attenuates infectivity of SARS-CoV and other coronaviruses and is therefore an intriguing therapeutic strategy for coronavirus infections. Lithium, a widely used medication, directly inhibits GSK-3 and impairs N phosphorylation, viral transcription, replication, and infectivity of diverse coronaviruses. However, GSK-3 phosphorylation of N protein from SARS-CoV-2 (the cause of COVID19) has not been reported. This proposal leverages our long-standing expertise with GSK-3 to block N function and SARS-CoV-2 replication. In a preliminary review of 70,000 subjects undergoing PCR testing for SARS- CoV-2, we found that patients on lithium had reduced risk of COVID19 (odds ration = 0.5 [0.36 - 0.80], p = 0.0002). We show that phosphorylation of N from SARS-CoV-2 is inhibited by lithium and that other GSK-3 inhibitors block N phosphorylation with IC50s in the low micromolar range. GSK3 loss of function supports that GSK-3 is required for SARS-CoV-2 N protein phosphorlyation. We identified clinically-tolerated drugs that unexpectedly inhibit GSK-3 and impair N phosphorylation at clinically-tolerated levels. Aim 1 of this proposal describes approaches to enhance inhibition of N phosphorylation by lithium and by selective GSK-3 inhibitors, with a focus on those shown to be safe in humans through clinical trials for other diseases. As GSK-3 phosphorylation of N protein requires pre-phosphorylation at a distinct site by another, unkown protein kinase, Aim 2 will identify and target the priming kinase as an alternative strategy to block SARS-CoV-2 transcription and replication. This aim will also test whether inhibitors of either GSK-3 or the priming kinase interfere with replication of other pathogenic coronaviruses. If successful, the project will identify clinically safe medications that can be repurposed to treat COVID19 as well as future coronavirus outbreaks.

总结