Optimization of a computationally designed antiviral for influenza

计算设计的流感抗病毒药物的优化

• 批准号: 9046012
• 负责人: Deborah H. Fuller
• 金额: $ 20.94万
• 依托单位: VIRVIO, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046012
• 关键词: Adverse effects; Affinity; Amino Acids; Antiviral Agents; Binding; Binding Proteins; Biological Availability; Cause of Death; Cessation of life; Computer Simulation; Computing Methodologies; Data; Development; Disease; Dose; Drug resistance; Elderly; Future; General Population; Hemagglutinin; Hospitalization; Human; Immune; Immune response; In Vitro; Infection; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Lead; Longevity; Marketing; Mediating; Medical; Methods; Morbidity - disease rate; Mus; Pathogenesis; Peptides; Population; Protein Engineering; Proteins; Public Health; Recovery; Resistance; Therapeutic; Time; Vaccination; Variant; Viral; Virus; Work; cost; design; flu; in vivo; influenza virus vaccine; influenzavirus; innovation; mucosal site; novel; pandemic disease; pandemic influenza; pre-clinical; prevent; prophylactic; public health relevance; receptor; research study; resistant strain; seasonal influenza; stem

 DESCRIPTION (provided by applicant): Influenza is a leading cause of death and morbidity in the US, resulting in up to 40,000 deaths, ~200,000 hospitalizations and > $10.4 billion in expenses per year. Current antivirals incur high resistance rates and have low efficacy so there is a crucial need to develop better approaches to protect from seasonal influenza and future pandemics. We aim to develop computationally designed peptides as a pre-exposure prophylactic and post-exposure therapeutic against influenza. We have shown that a small computationally designed protein (HB36.6), interferes with influenza infection by binding the highly conserved hemagglutinin stem region and neutralizes a wide range of influenza variants including pandemic strains and strains resistant to current antivirals. When delivered intranasally, this influenza binder confers complete prophylactic and therapeutic protection against different influenza strains in mice, a result that demonstrates for the first time, transformation of a theoretical target designed by this computational method into a new antiviral with strong biopotency in vivo. In this application, we propose to build on our promising findings with HB36.6 and broaden efficacy by computationally designing de novo hyperstable mini-protein binders (30-40 amino acids) that will be effective against influenza providing pan-specific protection against a broader range of influenza strains. These new hyperstable mini-binders, will be smaller, more stable, have increased bioavailability, and will have a lower cost of manufacturing than our current lead Group 1 binder HB36.6. We hypothesize that the optimized computationally designed mini-protein binders will afford superior broad, potent prophylactic and therapeutic protection in mice against Group 1 viruses. We will determine expression and in vitro neutralization of computationally designed mini-proteins and identify a single mini-protein binder that affords the best prophylactic and therapeutic protection in mice challenged with a lethal dose of Group 1 influenza virus. If successful, these experiments will establish a new class of flu antivirals that could overcome the limitations of currently marketed flu antivirals an build a strong preclinical data package for future development.

 描述（由适用提供）：流感是美国的主要死亡和发病率的主要原因，导致多达40,000人死亡，约20万次住院和每年> 104亿美元的费用。当前的抗病毒药会产生高电阻率，并且效率低，因此至关重要的是开发更好的方法来保护季节性影响者和未来的大流行。我们旨在开发计算设计的肽作为针对影响力的预防性预防和暴露后治疗。我们已经表明，一种小型计算设计的蛋白质（HB36.6）通过结合高度保守的血凝素茎区域来干扰影响者感染，并中和广泛的有影响力的变体，包括大流行菌株和对当前抗病毒药的抗性。当鼻内传递时，这种影响者粘合剂承认了针对小鼠不同影响的完全预防性和治疗保护，这一结果证明了该计算方法设计的理论靶标转化为一种新的抗病毒药，并在体内具有强大的生物态。在此应用程序中，我们建议以HB36.6的承诺结果为基础，并通过计算设计从头设计的Min-protein Binders（30-40氨基酸）来扩大效力 防止更广泛的影响力菌株。这些新的Hyperstable Mini-Binders将更小，更稳定，具有生物利用度的增加，并且制造成本将比我们目前的铅1组HB36.6低。我们假设经过优化的计算设计的迷你蛋白质粘合剂将在小鼠针对1组病毒的小鼠中提供超广泛，有效的预防和治疗保护。我们将确定计算设计的迷你蛋白质的表达和体外中和，并确定单一的微型蛋白质粘合剂，该粘合剂提供了最佳的预防性和治疗性保护，这在受1组1的致命剂量影响的小鼠中提供了挑战。如果成功的话，这些实验将建立一类新的流感抗病毒药，这些抗病毒药可以克服当前销售的流感抗病毒药的局限性，建立了一个强大的临床前数据包，以供将来开发。