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

这项小企业创新研究（SBIR）第一阶段项目的更广泛影响将来自开发安全、可持续的COVID-19抗病毒治疗方法。疫苗和药物的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，特别是对高危人群的安全性，仍然令人担忧。拟议的项目是一种抗病毒吸入器，它提供一种天然的免疫防御唾液蛋白，可以阻断肺中病毒复制所必需的分子的活性。对于健康受损的人来说，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，治疗目标是病毒基因组复制过程。因此，这种靶向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有效性。其次，它不需要临床给药，因此患者更容易获得。第三，这种疗法有潜力成为一种广泛的抗病毒疗法。拟议的项目将验证针对SARS-CoV-2的新型抗病毒治疗方法。首先，将在一个基于细胞的模型中验证抗病毒作用，该模型模拟感染冠状病毒的人肺、在气液界面培养的肺泡上皮细胞和感染SARS-CoV-2的人肺。接下来，将使用体内模型来证实该疗法可以到达肺部的病毒靶点，被肺泡上皮细胞摄取，并避免肺部递送的障碍（如粘液、肺酶或巨噬细胞）。最后，该项目将证实该疗法不会引起促炎反应和肺细胞毒性，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。治疗将通过吸入，并最终成为一种治疗和预防性抗病毒吸入器。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 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.