SBIR Phase I: Development of a novel peptide inhibitor of coronavirus papain-like protease as a prophylactic and anti-viral therapeutic for COVID19, administered by inhalation

小企业创新研究第一阶段项目的更广泛影响将来自为新冠肺炎开发安全和可持续的抗病毒治疗。疫苗和药物开发工作正在进行中，但这些治疗方法的有效性及其安全性仍然令人担忧，特别是对高危人群。拟议的项目是一种抗病毒吸入器，它可以提供一种天然的免疫防御唾液蛋白，这种蛋白可以阻止一种对病毒在肺部复制至关重要的分子的活动。对于健康状况不佳的人来说，候选疗法可能是一种更安全的治疗选择。这种治疗的可持续性取决于三个因素。首先，治疗的目标是病毒基因组复制过程。因此，这项有针对性的技术不会受到病毒突变的影响，并将保持其对当前和未来冠状病毒爆发的效力。其次，它不需要临床给药，因此更容易为患者所用。第三，该疗法作为一种广泛的抗病毒疗法具有潜力。拟议的项目将验证一种针对SARS-CoV-2的新型抗病毒疗法。首先，抗病毒作用将在模拟人类肺部感染冠状病毒的细胞模型中得到验证，肺泡上皮细胞在气液界面培养并感染SARS-CoV-2。接下来，将使用体内模型来确认治疗可以到达肺中的病毒靶点，经历肺泡上皮细胞的摄取，并避开肺部递送的障碍(例如粘液、肺酶或巨噬细胞)。最后，该项目将证实，该疗法不会在肺细胞中引发促炎反应和毒性，因此可以安全地给予健康受损的人，而不会加剧他们的免疫反应。该治疗将通过吸入进行，并最终成为一种治疗性和预防性的抗病毒吸入器。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact of this Small Business Innovation Research (SBIR) Phase I project will result from development of a safe and sustainable anti-viral treatment for COVID-19. Vaccine and drug development efforts are underway, but the efficacy of these treatments and their safety particularly for high-risk populations remain a concern. The proposed project is an anti-viral inhaler that delivers a natural immune defense salivary protein that blocks the activity of a molecule essential for viral replication in the lung. The candidate therapeutic will potentially be a safer treatment option for people with compromised health. The sustainability of this treatment relies on three factors. First, the therapeutic targets a viral genome replication process. Thus, this targeted technology will not be compromised by virus mutations and will maintain its efficacy against current and future coronavirus outbreaks. Second, it does not require clinical administration and is thus more easily accessible by patients. Third, the treatment has potential as an broad anti-viral therapy.The proposed project will validate a novel anti-viral treatment against SARS-CoV-2. First, the anti-viral action will be validated in a cell-based model that mimics human lung infected with coronavirus, alveolar epithelial cells cultured in an air-liquid interface and infected with SARS-CoV-2. Next, an in vivo model will be used to confirm that the therapy can reach the virus target site in the lung, undergo uptake by the alveolar epithelial cells and avoid the barriers of pulmonary delivery (e.g. mucus, pulmonary enzymes or macrophages). Finally, this project will confirm that the therapy does not elicit a pro-inflammatory response and toxicity in lung cells, so it can be safely given to people with compromised health without exacerbating their immune response. The treatment will be delivered by inhalation and ultimately become a therapeutic and prophylactic anti-viral inhaler.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.