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.