Developing Lectins as Inhibitors of Coronavirus Spike Proteins

开发凝集素作为冠状病毒刺突蛋白的抑制剂

基本信息

批准号：
10428203
负责人：
Alex Joseph Guseman
金额：
$ 10万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10428203
关键词：
2019-nCoV ACE2 Animal Model Antibodies Award Binding Biochemical Biological Assay Biophysics Burkholderia COVID-19 COVID-19 vaccine Cells Cessation of life Clinic Communication Coronavirus Coronavirus spike protein Dangerousness Data Development Development Plans Diagnostic Disease Educational workshop Electron Microscopy FDA Emergency Use Authorization Family Future Glycoproteins Grant HIV Health Health Personnel Human Immune Incentives Infection Intervention Knowledge Lead Lectin Left Lilium Link Mannose Mediating Membrane Fusion Mentorship Middle East Respiratory Syndrome Coronavirus Molecular Conformation Molecular Sieve Chromatography Mutation Pharmacologic Substance Phase Polysaccharides Process Proteins Research Resources Respiratory Disease Risk SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 spike protein SARS-CoV-2 variant Science Solvents Spanish flu Specificity Structure Surface Testing Therapeutic Therapeutic antibodies Training Treatment Efficacy Universities Vaccination Vaccine Research Vaccines Variant Viral Viral Genome Virion Virus Virus Diseases Work Writing betacoronavirus carbohydrate binding protein career career development combat convalescent plasma design experimental study fight against glycosylation gp-120 Antigen human coronavirus inhibitor instrumentation knowledge of results light scattering member nanomolar neutralizing antibody novel novel coronavirus pandemic disease prevent receptor receptor binding skills structural biology symposium variants of concern viral entry inhibitor virology weapons

项目摘要

Project Summary/Abstract In late 2019, the SARS-CoV2 virus emerged as a global pandemic, causing the severe respiratory disease COVID-19 and resulting in millions of deaths worldwide. As a coronavirus, SARS-CoV2 host interactions are dictated through the Spike proteins that encompass the virion. The Spike protein of SARS-CoV2, is a highly glycosylated trimer that interacts with the ACE2 receptor on host cells via the receptor binding domain (RBD) to facilitate viral entry. As a key player in viral infection, the Spike trimer, and the RBD, have become the target for a majority of approved therapeutics and vaccines used to treat or prevent SARS-CoV2. In this proposal, the PI uses a novel antiviral lectin, BOA, which he has demonstrated that BOA binds glycans on the spike protein, and inhibits SARS-CoV2 viral entry. To understand how BOA inhibits viral entry, during the K99 phase of the award, the PI will determine the mechanism by which BOA inhibits in SARS-CoV2 viral infection using a combination of viral inhibition assays, biophysical assays, and electron microscopy. Subsequently the PI will test the ability of BOA to inhibit emerging SARS-CoV2 variants of concern that have accumulated mutations to various regions of the spike protein that facilitate immune escape. Expanding upon these findings during the independent R00 phase of this award, the PI will use skills developed during the K99 phase to establish his own independent research group, where they will test the ability of the BOA lectin to inhibit viral entry of Beta- Coronaviruses known to infect humans. Successful completion of these aims could provide a bona fide broad spectrum coronavirus inhibitor to be further developed as a therapeutic or diagnostic for the next coronavirus that emerges. The proposed research, will provide the PI with new and exciting training in virology as well as electron microscopy which he intends to pass on to his future trainees. The proposed work will be completed at The University of Pittsburgh, where the Department of Structural Biology and Center for Vaccine Research will provide unmatched access to resources, instrumentation, and experts in the field. The PI has assembled an exciting mentorship team of virologists and biophysicists who he will meet with monthly to receive advice, discuss results, designed new experiments, and prepare for transitioning into an independent career. To aide in his career development, the university offers numerous workshops to develop skills such as grant writing and mentorship. The PI will also attend conferences to give presentations and hone his science communications skills. In Summary, the proposed training and career development plans will prepare the PI to lead his own independent research group and become a leader in his field.

项目摘要/摘要 2019年底，SARS-COV2病毒成为全球性大流行，导致严重的呼吸系统疾病 Covid-19，并导致全球数百万人死亡。作为冠状病毒，SARS-COV2主机相互作用是通过包含病毒粒子的尖峰蛋白决定。 SARS-COV2的尖峰蛋白是高度通过受体结合结构域（RBD）与宿主细胞上ACE2受体相互作用的糖基化三聚体（RBD）促进病毒进入。作为病毒感染的关键参与者，Spike Trimer和RBD已成为目标对于大多数批准的治疗和疫苗，用于治疗或预防SARS-COV2。在此提案中， PI使用一种新型的抗病毒凝集素BOA，他证明BOA在尖峰蛋白上结合聚糖，并抑制SARS-COV2病毒进入。要了解BOA如何抑制病毒的进入，在K99阶段奖励，PI将确定BOA使用A抑制SARS-COV2病毒感染的机制病毒抑制测定，生物物理测定和电子显微镜的组合。随后PI将测试BOA抑制关注的新兴SARS-COV2变体的能力，这些变体积累了突变尖峰蛋白的各个区域，促进免疫逃逸。在这些发现中扩展该奖项的独立R00阶段，PI将使用在K99阶段开发的技能来建立他的自己的独立研究小组，他们将测试BOA凝集素抑制β- 冠状病毒感染了人类。这些目标的成功完成可能会提供真正的广泛光谱冠状病毒抑制剂将作为下一个冠状病毒的治疗或诊断进一步开发出现了。拟议的研究将为PI提供有关病毒学的新培训以及他打算将电子显微镜传递给未来的学员。拟议的工作将在匹兹堡大学，结构生物学系和疫苗研究中心将提供对现场资源，工具和专家的无与伦比的访问权限。 PI组装了激动人心的病毒学家和生物物理学家的指导团队，他将每月见面以收到建议，讨论结果，设计新的实验，并为过渡到独立职业做准备。助手在他的职业发展中，该大学提供了许多研讨会来发展技能，例如赠款写作和指导。 PI还将参加会议以进行演讲并磨练他的科学沟通技巧。总而言之，拟议的培训和职业发展计划将为PI做准备领导自己的独立研究小组，并成为该领域的领导者。