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

SARS-CoV-2引起新型冠状病毒传染病2019 （COVID-19）。SARS-CoV-2大流行的一个关键挑战是制定可以减缓疾病传播的保护性对策。在化学学部大分子、超分子和纳米化学项目的资助下，杜克大学的斯蒂芬·l·克雷格（Stephen L. Craig）和迈克尔·鲁宾斯坦（Michael Rubinstein）教授以及麻省理工学院的布拉德利·d·奥尔森（Bradley D. Olsen）教授正在开发用于吸入对策的大分子，以降低SARS-CoV-2的感染率。黏液清除是哺乳动物肺部重要的防御机制。它用于从气道表面捕获和清除吸入的传染性病原体，如SARS-CoV-2病毒。该团队制备了由许多由共价键连接的重复单元组成的大分子或聚合物。这些大分子是为了模仿人体内粘蛋白的特性而构建的。此外，合成的粘蛋白模拟物被标记为特异性针对SARS-CoV-2的粘合剂。制备的模拟黏液聚合物被设计为一旦引入体内就能有效地与天然黏液混合。这使得聚合物可以作为有效的诱饵，与SARS-CoV-2中的病毒受体结合。结果，病毒进入肺部并感染细胞的途径被阻断。除了合成化学之外，本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展可能对暴露于大剂量SARS-CoV-2的医护人员特别有用，但也可能扩大到平民人口。该项目还有助于在高度跨学科的研究环境中培养博士后。研究小组正在开发强化粘膜层的吸入聚合对策，使个体在接触新冠病毒后，感染率大幅下降，或在不出现严重症状的情况下耐受更大剂量的新冠病毒。在第一个项目目标中，利用钌催化开环复分解聚合合成了新的瓶刷聚合物，这些聚合物具有现成的木犀草素、槲皮素和头孢酞基复合物，用于SARS-CoV-2。然后进行了系统的研究，探索配体和聚合物设计如何影响它们的多病毒结合理论和实验。第二个目标是了解模拟粘蛋白的瓶刷聚合物如何融入由天然粘蛋白形成的超分子网络，以及它们如何在减少病毒渗透的同时保持这些自然系统的关键机制特性。结合、网络形成、微相分离和宏观相分离的概率使用改进的分子模型进行预测。细胞片测试用于量化黏液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偶联方案来推进瓶刷聚合物的设计，使sars - cov -2特异性配体能够附着在瓶刷聚合物上。研究人员还开发了新的理论和模拟方法，用于病毒扩散和合成瓶刷与天然粘蛋白的混合，这可能适用于其他生物系统。这笔拨款是使用《冠状病毒援助、救济和经济安全（关怀）法案》分配给MPS的补充资金提供的资金。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。

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.