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

• 批准号: 10672446
• 负责人: DAVID BAKER
• 金额: $ 70.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10672446
• 关键词: 2019-nCoV; ACE2; Acute; Acute Respiratory Distress Syndrome; Aerosols; Affinity; Animals; Anti-Inflammatory Agents; Antibodies; Antiviral Agents; Avidity; Binding; Binding Proteins; Binding Sites; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19 therapeutics; COVID-19 treatment; Capillary Leak Syndrome; Cells; Computing Methodologies; Coupled; Cytokine Receptors; Development; Disease; Disease Outbreaks; Drug Compounding; Drug Kinetics; Endothelial Cells; Epithelial Cells; Escherichia coli; Genetic; Glycoproteins; Goals; High Performance Computing; Human; IL1R1 gene; 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; Viral Physiology; Virus; Virus Diseases; Work; antagonist; anti-viral efficacy; clinical development; cost; cytokine; cytokine release syndrome; design; disability; economic behavior; economic impact; efficacy evaluation; emerging pathogen; future pandemic; immunogenicity; improved; in vivo; inhibitor; innovation; manufacture; mimetics; neglect; novel; novel coronavirus; 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

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.

项目总结

项目成果

Structure, receptor recognition, and antigenicity of the human coronavirus CCoV-HuPn-2018 spike glycoprotein.

• DOI: 10.1016/j.cell.2022.05.019
• 发表时间: 2022-06-23
• 期刊: CELL
• 影响因子: 64.5
• 作者: Tortorici, M. Alejandra;Walls, Alexandra C.;Joshi, Anshu;Park, Young-Jun;Eguia, Rachel T.;Miranda, Marcos C.;Kepl, Elizabeth;Dosey, Annie;Stevens-Ayers, Terry;Boeckh, Michael J.;Telenti, Amalio;Lanzavecchia, Antonio;King, Neil P.;Corti, Davide;Bloom, Jesse D.;Veesler, David
• 通讯作者: Veesler, David