RAPID: Rational Design of Biomimetic Virus-Trapping Polymers

第一部分：非技术概述SARS-CoV-2病毒已在全球造成深刻影响。它的高传染性使它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、感染性休克和重要器官衰竭，包括肝脏和肾脏。在缺乏有效疫苗或治疗剂的情况下，减少人群接触病毒是预防感染和使卫生保健系统负担过重的唯一可行策略。SARS-CoV-2的传播途径多种多样。预防SARS-CoV-2的传播需要针对所有传播方式的有效和易于使用的技术。这项快速反应研究（Rapid）资助由数学和物理科学理事会材料研究部生物材料项目资助，并由生物科学理事会分子和细胞生物科学部分子生物物理项目共同资助，支持开发利用SARS-CoV-2的碳水化合物结合特性来固定病毒的仿生聚合物的研究。开发的聚合物将用于生产病毒固定化凝胶和表面，用于保护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：技术概述SARS-CoV-2病毒由包裹在核衣壳蛋白中的单链RNA组成。这个病毒核心被一层脂质膜包围，脂质膜内嵌有三种蛋白质：包膜蛋白、膜蛋白和刺突蛋白，刺突蛋白负责与宿主细胞受体结合并进入宿主细胞。S蛋白最近被证明与糖胺聚糖（GAG）肝素结合。本项目将模拟、合成和表征相结合，采用正馈和反馈相结合的方法，合理设计用于固定SARS-CoV-2病毒粒子的碳水化合物共轭聚合物。计算机模拟将侧重于确定优选的GAG结构和S蛋白结合区域的拓扑结构，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络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聚开环聚合、自缩聚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法、表面等离子体共振光谱法和带有耗散监测的石英晶体微重力法来完成。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.