De Novo Design of Minibinder Antagonists for COVID-19 and Future Pandemics

针对 COVID-19 和未来大流行病的 Minibinder 拮抗剂的从头设计

基本信息

批准号：
10460648
负责人：
DAVID BAKER
金额：
$ 71.39万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2021-08-02 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10460648
关键词：
2019-nCoV ACE2 Acute Acute Respiratory Distress Syndrome Aerosols Affinity Animals Anti-Inflammatory Agents Antibodies Antiviral Agents Avidity Binding Binding Sites COVID-19 COVID-19 mortality COVID-19 pandemic COVID-19 therapeutics COVID-19 treatment Capillary Leak Syndrome Cells Computing Methodologies Coronavirus Coupled Cytokine Receptors Development Disease Disease Outbreaks Drug Compounding Drug Kinetics Endothelial Cells Epithelial Cells Escherichia coli Future Genetic Glycoproteins Goals High Performance Computing Human Infection Inflammatory Inflammatory Response Influenza Hemagglutinin Interleukin 2 Receptor Interleukin-1 beta Interleukin-2 Interleukin-6 Interleukins Intravenous K-18 conjugate Lead Life Mesocricetus auratus Methods Mission Modeling Monoclonal Antibodies Mus Nebulizer Organ failure Outcome Peptides Pharmaceutical Preparations Phase I Clinical Trials Protein Engineering Proteins Protocols documentation Public Health Research Rodent Model Route SARS-CoV-2 infection SARS-CoV-2 spike protein Safety Sepsis Signal Transduction Social Behavior Specificity System Testing Therapeutic United States National Institutes of Health Viral Virus Virus Diseases Work antagonist anti-viral efficacy clinical development cost cytokine cytokine release syndrome design disability emerging pathogen immunogenicity improved in vivo inhibitor innovation mimetics neglect novel novel therapeutics pandemic disease parallel computer pathogen pathogen genome preclinical development prophylactic public health priorities rational design receptor receptor binding small molecule subcutaneous therapeutic protein therapeutically effective vaccine development

项目摘要

PROJECT SUMMARY One of the most pressing public health priorities for the COVID-19 pandemic is the development of an effective and inexpensive therapeutic. The long-term goal of this proposal is to develop such COVID-19 treatments, as well as the methods needed to rapidly create such molecules as soon as any new pathogen is identified. The central hypothesis is that computational design can be used to quickly create proteins with potent antiviral activity and others that suppress “cytokine storms” associated with advanced infection. Such countermeasures, if rapidly developed and deployed, could save millions of lives during an outbreak until vaccines are developed. The specific aims are to: 1) overcome current limitations in the discovery and development of protein therapeutics by creating methods for the de novo design of hyper-stable miniproteins that bind tightly to vulnerable binding sites on the SARS-CoV-2 Spike glycoprotein, including the receptor binding domain (RBD) of the ACE-2 cellular receptor and the fusion peptide region; 2) Enhance the avidity of such anti-Spike minibinders through genetic fusion of multiple copies, or through rational design of higher-order oligomers to create drug compounds that are less prone to viral mutagenic escape; 3) Apply the same minibinder design pipeline to create cytokine receptor antagonists of key cytokines IL-6 and IL-1β likely involved in acute respiratory distress syndrome (ADRS) associated with COVID-19 mortality; 4) Assess the efficacy of antiviral and anti-interleukin minibinders by several routes of delivery (intravenous, intranasal and subcutaneous) in rodent models of COVID-19 and assess immunogenicity in order to identify those designs best suited for further preclinical development. As proof of principle, the first anti-Spike minibinders have already been designed, were found to bind to SARS-CoV-2 Spike RBD, and were found to neutralize live virus with activities rivaling the most potent known antibodies. This proposal is innovative because it seeks to apply powerful emerging methods in the computational design of new protein therapeutics to the COVID-19 pandemic. The proposal is significant because it would be the first example of computational protein design yielding potent and entirely de novo antiviral and anti-inflammatory therapeutics for an active pandemic. Ultimately, rapid minibinder design methods have the potential to generate treatments for future pandemics, as well as for many other common and neglected diseases and conditions.

项目概要 COVID-19 大流行最紧迫的公共卫生优先事项之一是制定有效的该提案的长期目标是开发此类 COVID-19 治疗方法，例如以及一旦发现任何新病原体就快速创建此类分子所需的方法。中心假设是计算设计可用于快速创建具有有效抗病毒活性的蛋白质以及其他抑制与晚期感染相关的“细胞因子风暴”的措施，如果迅速的话。在疫苗开发出来之前，疫苗的开发和部署可以在疫情爆发期间挽救数百万人的生命。具体目标是：1）克服目前治疗性蛋白质发现和开发的局限性创建从头设计超稳定微型蛋白的方法，这些微型蛋白与脆弱的结合位点紧密结合 SARS-CoV-2 Spike 糖蛋白，包括 ACE-2 细胞的受体结合域 (RBD) 受体和融合肽区域；2)通过遗传增强此类抗Spike微型结合剂的亲合力多个拷贝的融合，或通过合理设计高阶寡聚物来创建药物化合物 3) 应用相同的minibinder设计流程来创建细胞因子受体可能与急性呼吸窘迫综合征 (ADRS) 相关的关键细胞因子 IL-6 和 IL-1β 的拮抗剂与 COVID-19 死亡率相关；4) 评估多种抗病毒药物和抗白细胞介素微型结合剂的功效 COVID-19 啮齿动物模型中的给药途径（静脉内、鼻内和皮下）并评估免疫原性，以确定最适合进一步临床前开发的设计。原则上，第一个抗 Spike 微型结合剂已经设计出来，被发现可以与 SARS-CoV-2 Spike 结合 RBD，被发现可以中和活病毒，其活性可与最有效的已知抗体相媲美。该提案具有创新性，因为它寻求在新的计算设计中应用强大的新兴方法该提案意义重大，因为这将是第一个例子。计算蛋白质设计产生有效且完全从头的抗病毒和抗炎疗法最终，快速微型粘合剂设计方法有可能产生治疗方法。预防未来的流行病，以及许多其他常见和被忽视的疾病和状况。