RAPID: Rational Design of Biomimetic Virus-Trapping Polymers

RAPID：仿生病毒捕获聚合物的合理设计

• 批准号: 2034567
• 负责人: Maren Roman
• 金额: $ 20万
• 依托单位: Virginia Polytechnic Institute and State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2034567&HistoricalAwards=false
• 关键词: RAPID; Rational; Design; Biomimetic; Virus

PART 1: NON-TECHNICAL SUMMARYThe SARS-CoV-2 virus has caused a pandemic of profound global impact. Its high infectivity enabled it to spread rapidly across the world. In severe cases, infection with SARS-CoV-2 leads to respiratory failure, septic shock, and failure of vital organs, including the liver and kidneys. In the absence of an effective vaccine or therapeutic agent, reducing the population’s exposure to the virus is the only viable strategy for preventing infections and overburdening of the health care system. Transmission of SARS-CoV-2 occurs through multiple routes. Prevention of SARS-CoV-2 transmission requires effective and easy-to-use technologies directed against all modes of transmission. Funded by the Biomaterials Program in the Division of Materials Research of the Mathematical and Physical Sciences Directorate, and cofunded by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences of the Biological Sciences Directorate, this Rapid Response Research (RAPID) grant supports research into the development of biomimetic polymers that exploit the carbohydrate-binding properties of SARS-CoV-2 for virus immobilization. The developed polymers will be designed to produce virus-immobilizing gels and surfaces for applications in protective formulations and devices as well as functional studies, isolation, and purification of virions in scientific settings. The research serves the national interest by advancing the science of biomimetic materials and developing materials for the improvement of national health. PART 2: TECHNICAL SUMMARYThe SARS-CoV-2 virus consists of single-stranded RNA that is enclosed in the nucleocapsid protein. This viral core is surrounded by a lipid membrane with three embedded proteins: the envelope protein, the membrane protein, and the spike (S) protein, which is responsible for binding to host cell receptors and host cell entry. The S protein has recently been shown to bind to the glycosaminoglycan (GAG) heparin. This project will integrate simulation, synthesis, and characterization in a forward- and backward-feeding loop approach to rationally design carbohydrate-conjugated polymers for immobilization of SARS-CoV-2 virions. Computer simulations will focus on defining the preferred GAG structures and topology of the S protein binding regions and will include structure modeling of the S protein, molecular docking of GAG oligosaccharides to the S protein, and molecular dynamics simulation of the co-complexes. Synthesis strategies toward GAG-conjugated polymers will include self-condensing ring-opening polymerization, self-condensing vinyl polymerization, and surface-initiated polymerization. Characterization and quantification of binding to the S-protein will be done by biolayer interferometry, surface plasmon resonance spectroscopy, and quartz crystal microgravimetry with dissipation monitoring.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

第 1 部分：非技术摘要 SARS-CoV-2 病毒引发了一场具有深远全球影响的大流行。其高传染性使其能够在世界范围内迅速传播。在严重的情况下，感染 SARS-CoV-2 会导致呼吸衰竭、感染性休克以及包括肝脏和肾脏在内的重要器官衰竭。在缺乏有效疫苗或治疗剂的情况下，减少人群对病毒的接触是预防感染和医疗保健系统负担过重的唯一可行策略。 SARS-CoV-2 的传播通过多种途径进行。预防 SARS-CoV-2 传播需要针对所有传播方式的有效且易于使用的技术。这项快速响应研究 (RAPID) 拨款由数学和物理科学局材料研究司生物材料项目资助，并由生物科学局分子和细胞生物科学司分子生物物理学项目共同资助，支持利用 SARS-CoV-2 的碳水化合物结合特性来治疗病毒的仿生聚合物的开发研究 固定化。所开发的聚合物将被设计用于生产病毒固定凝胶和表面，用于保护性配方和设备以及科学环境中病毒粒子的功能研究、分离和纯化。该研究通过推进仿生材料科学和开发改善国民健康的材料来服务于国家利益。 第 2 部分：技术摘要 SARS-CoV-2 病毒由包裹在核衣壳蛋白中的单链 RNA 组成。该病毒核心被脂质膜包围，脂质膜具有三种嵌入蛋白：包膜蛋白、膜蛋白和刺突 (S) 蛋白，刺突蛋白负责与宿主细胞受体结合并进入宿主细胞。最近显示 S 蛋白可与糖胺聚糖 (GAG) 肝素结合。该项目将在前向和后向馈送循环方法中整合模拟、合成和表征，以合理设计用于固定 SARS-CoV-2 病毒体的碳水化合物缀合聚合物。计算机模拟将侧重于定义 S 蛋白结合区域的首选 GAG 结构和拓扑，并将包括 S 蛋白的结构建模、GAG 寡糖与 S 蛋白的分子对接以及共复合物的分子动力学模拟。 GAG共轭聚合物的合成策略包括自缩合开环聚合、自缩合乙烯基聚合和表面引发聚合。与 S 蛋白结合的表征和定量将通过生物层干涉测量、表面等离子体共振光谱和具有耗散监测的石英晶体微重力测量来完成。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。