RAPID: Collaborative Research: Augmenting Mucosal Gels with Associating Brush Polymers to Prevent COVID-19 Infection

RAPID：合作研究：用缔合刷状聚合物增强粘膜凝胶以预防 COVID-19 感染

• 批准号: 2029751
• 负责人: Bradley Olsen
• 金额: $ 10万
• 依托单位: Massachusetts Institute of Technology
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2029751&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2019年新型冠状病毒传染病（COVID-19）。 SARS-CoV-2大流行的一个关键挑战是制定保护性对策，以减缓疾病的传播。 在化学系大分子、超分子和纳米化学项目的资助下，斯蒂芬·L·杜克大学的克雷格和迈克尔·鲁宾斯坦以及布拉德利D.马萨诸塞州理工学院的Olsen博士正在开发大分子，用作吸入对策，以降低SARS-CoV-2的感染率。粘液清除是哺乳动物肺中的重要防御机制。 它用于捕获和清除呼吸道表面吸入的传染性病原体，如SARS-CoV-2病毒。 该团队制备了由许多通过共价键连接的重复单元组成的大分子或聚合物。 构建这些大分子是为了模拟人体中粘蛋白的性质。 此外，合成的粘蛋白模拟物用对SARS-CoV-2特异性的结合剂标记。 所制备的粘液模拟聚合物被设计成一旦引入体内就与天然粘液有效地混合。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。 因此，病毒进入肺部并感染细胞的途径被阻断。 除了合成化学，计算模型也用于本研究中，以指导和加快实验设计。 与这项研究相关的科学进步可能对暴露于大剂量SARS-CoV-2的卫生保健工作者特别有用，但也可能扩大到平民群体。 该项目还有助于在高度跨学科的研究环境中培养博士后学生。研究小组正在开发一种吸入聚合物对策，该对策将加强粘膜层，使个人能够在暴露后证明SARS-CoV-2感染率大幅下降，或者耐受更大剂量而不出现严重症状。在第一个项目目标中，使用钌催化的开环易位聚合合成了新的瓶刷聚合物，其用容易获得的基于毛地黄黄酮、槲皮素和头孢拉汀的SARS-CoV-2粘合剂官能化。 然后进行系统的研究，探索如何配体和聚合物的设计影响其多病毒结合使用理论和实验。 第二个目标是了解粘蛋白模拟瓶刷聚合物如何结合到由天然粘蛋白形成的超分子网络中，以及它们如何在减少病毒渗透的同时保持这些天然系统的关键机械特性。 关联，网络形成，微观相分离，宏观相分离的概率预测使用修改后的分子模型。 细胞片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缀合方案来推进瓶刷聚合物的设计，该方案使SARS-CoV-2特异性配体能够连接到瓶刷聚合物上。还针对病毒扩散以及合成瓶刷和天然粘蛋白的混合开发了新颖的理论和模拟方法，这些方法可适用于其他生物系统。该赠款是使用冠状病毒援助组织、救济组织、经济安全（CARES）该奖项反映了NSF的法定使命，并通过使用基金会的学术价值和更广泛的影响审查标准。