RAPID: Collaborative Research: Augmenting Mucosal Gels with Associating Brush Polymers to Prevent COVID19 Infection

RAPID：合作研究：用缔合刷状聚合物增强粘膜凝胶以预防新冠病毒感染

• 批准号: 2029760
• 负责人: Stephen Craig
• 金额: $ 10万
• 依托单位: Duke 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: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2029760&HistoricalAwards=false
• 关键词: RAPID; Collaborative; Research; Augmenting; Mucosal

The SARS-CoV-2 causes the novel coronavirus infectious disease 2019 (COVID-19). A key challenge with the SARS-CoV-2 pandemic is developing protective countermeasures that can slow the spread of the disease. With funding from the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Professors Stephen L. Craig and Michael Rubinstein of Duke University and Bradley D. Olsen of the Massachusetts Institute of Technology are developing macromolecules for use as inhaled countermeasures to reduce the rate of infection with SARS-CoV-2. Mucus clearance is an essential defense mechanism in mammalian lungs. It is used to capture and clear inhaled infectious agents, such as SARS-CoV-2 virus, from airway surfaces. The team prepares macromolecules or polymers consisting of many repeating units linked with covalent bonds. These large molecules are constructed in order to mimic properties of mucins in the human body. Additionally, the synthetic mucin mimics are tagged with binders that are specific for SARS-CoV-2. The prepared mucus-mimicking polymers are designed to blend efficiently with natural mucus in the body once introduced. This allows the polymers to act as effective decoys that bind to viral receptors in SARS-CoV-2. As a result, the pathways by which the virus enters the lungs and infects cells are blocked. Apart from synthetic chemistry, computational modelling is also used in this research to guide and speed up experimental design. Scientific advances associated with this research could be particularly useful for health care workers who are exposed to a heavy dose of SARS-CoV-2, but may also be scaled to the civilian population. The project also contributes to the training of postdoctoral students in a highly interdisciplinary research environment.The research team is developing an inhaled polymeric countermeasure that will reinforce mucosal layers, enabling individuals to demonstrate a substantially decreased rate of infection from SARS-CoV-2 after exposure or to tolerate a larger dose without developing severe symptoms. In the first project goal, new bottlebrush polymers functionalized with readily available luteolin-, quercetin- and cepharantine-based binders for SARS-CoV-2 are synthesized using ruthenium catalyzed ring opening metathesis polymerization. Systematic studies are then conducted to explore how the ligand and polymer design affect their multi-virus binding using both theory and experiment. The second goal focuses on understanding how mucin-mimetic bottlebrush polymers incorporate into supramolecular networks formed by native mucins and how they can maintain key mechanistic properties of these natural systems while reducing viral penetration. The probability of association, network formation, microphase separation, and macroscopic phase separation is predicted using modified molecular models. Cell sheet testing is used to quantify the impact of the mucin-mimetic polymers on infectivity. This research has the potential to advance the design of bottlebrush polymers by expanding new ligand conjugation schemes that enable SARS-CoV-2-specific ligands to be attached to bottlebrush polymers. Novel methods of theory and simulation are also developed for both viral diffusion and blends of synthetic bottlebrushes and natural mucins, which could be applicable to other biological systems.This grant is being awarded using funds made available by the Coronavirus Aid, Relief, and Economic Security (CARES) Act supplemental funds allocated to MPS.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.

SARS-COV-2导致新型冠状病毒感染疾病2019（Covid-19）。 SARS-COV-2大流行的主要挑战是发展可以减慢疾病传播的保护性对策。 在化学部的大分子，超分子和纳米化学计划的资助下，杜克大学的斯蒂芬·克雷格（Stephen L.粘液清除是哺乳动物肺的重要防御机制。 它用于从气道表面捕获和清除吸入的感染剂，例如SARS-COV-2病毒。 该团队准备大分子或聚合物，包括许多与共价债券相关的重复单元。 这些大分子的构建是为了模仿粘蛋白在人体中的特性。 另外，合成粘蛋白模拟物被标记为特定于SARS-COV-2的粘合剂。 制备的仿制粘液聚合物的设计旨在有效地与体内的天然粘液混合。这使聚合物可以充当与SARS-COV-2中病毒受体结合的有效诱饵。 结果，病毒进入肺和感染细胞的途径被阻断。 除了合成化学外，这项研究还使用了计算建模来指导和加快实验设计。 与这项研究相关的科学进步对于暴露于大量SARS-COV-2但也可以扩展到平民的卫生保健工作者特别有用。 该项目还有助于在高度跨学科的研究环境中培训博士后生。研究小组正在开发吸入的聚合物对策，将增强粘膜层，使个人能够证明暴露后SARS-COV-2的感染率大大降低，或者在暴露后或耐受较大剂量而不会出现严重症状。在第一个项目目标中，使用氟森催化的环分解聚合合成，与易于使用的叶黄素，槲皮素和基于头孢烷基的粘合剂合成了新的瓶洗聚合物。 然后进行系统研究，以探索配体和聚合物设计如何使用理论和实验影响其多病毒结合。 第二个目标着重于了解粘蛋白模拟奶瓶聚合物如何融入由天然粘蛋白形成的超分子网络中，以及它们如何维持这些天然系统的关键机械性能，同时降低病毒渗透。 使用改良的分子模型预测关联，网络形成，微相分离和宏观分离的概率。 细胞板测试用于量化粘蛋白模拟聚合物对感染性的影响。 这项研究有可能通过扩展新的配体共轭方案来推动瓶洗聚合物的设计，从而使SARS-COV-2特异性配体能够连接到奶瓶刷聚合物。还开发了新颖的理论和模拟方法，用于病毒扩散和合成瓶洗涤和天然粘蛋白的混合物，可以适用于其他生物系统。这笔赠款是使用Coronavirus AID，救济，救济和经济安全（CARES）通过对MPS.的授予的授予的授予的授权和奖励的资金来授予的。基金会的智力优点和更广泛的影响审查标准。