SBIR Phase I: Stress Pathway Inhibition Prevents COVID-19 Infection (COVID-19)

小企业创新研究第一阶段项目的更广泛影响是追求为新冠肺炎开发一流、无毒、廉价和有效的治疗方法，适用于包括老年人在内的弱势患者和那些有癌症、高血压、糖尿病和肥胖症额外风险的患者。与正常细胞相比，这些情况会对患病细胞产生更高水平的压力。这个项目利用新冠肺炎使用与癌细胞用于生存的相同途径来增强病毒感染的见解；这个过程会导致免疫系统减弱，从而使肿瘤细胞和病毒繁殖。拟议的项目将通过探索这一生存途径如何增加新冠肺炎的传染性、削弱免疫系统和诱导肿瘤细胞耐药来创造创新的抗病毒疗法。它的用途可以扩展到其他新的靶点和疗法。这个SBIR第一阶段项目利用了对肿瘤和病毒感染之间相似性的见解。该项目将推动将一种新的抑制剂转化为一种生存因子，通过提高肿瘤存活率和增强病毒感染来持续防止这些伤口愈合。这种新型的抑制剂可以有效地阻断新冠肺炎尖峰蛋白与这种生存因子的结合，这种生存因子已被证明在癌症和其他炎症性疾病的应激肺细胞上高表达。该项目的目标是1)证明建议的新冠肺炎抑制剂可以阻断应激肺细胞对新冠肺炎的感染；2)减少细胞因子的表达，以减轻与新冠肺炎感染相关的细胞因子风暴；3)防止免疫减弱；4)抑制凝血障碍，以减轻“血液凝块风暴”。该项目将使用标准的体外病毒感染性分析和体内免疫能力强的荷瘤小鼠模型，感染一种致命的新冠肺炎菌株。综上所述，这些研究将证明，建议的领先生存因子抑制剂可以显著减少新冠肺炎病毒的附着、进入和复制，并在体外和体内降低受感染的肺泡上皮细胞的免疫抑制性质。该奖项反映了美国国家科学基金会的法定使命，并已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 is the pursuit of developing a first-in-class, non-toxic, inexpensive, and effective treatment for COVID-19 for vulnerable patients including the elderly and those at additional risk from cancer, high blood pressure, diabetes and obesity. These conditions produce high levels of stress on diseased cells compared to normal cells. This project leverages insights that COVID-19 uses the same pathway to enhance viral infection as cancer cells use for survival; this process causes immune system weakening which allows tumor cells and viruses to multiply. The proposed project will create innovative anti-viral therapies by exploring how this survival pathway increases COVID-19 infectivity, weakens the immune system and induces tumor cell resistance. Its use can be expanded to other new targets and therapies. This SBIR Phase I project leverages insights regarding similarities between tumors and viral infections. This project will advance translation of a novel inhibitor to a survival factor that continually keeps these wounds from healing by increasing tumor survival and enhancing viral infections. This novel inhibitor can potently block the binding of COVID-19 spike protein to this survival factor, which has been shown to be highly expressed on stressed lung cells as a result of cancer and other inflammatory diseases. The goals of this project are to 1) show that the proposed COVID-19 inhibitor can block COVID-19 infection of stressed lung cells; 2) reduce cytokine expression to lessen the cytokine storm associated with COVID-19 infection; 3) prevent immune weakening and 4) inhibit coagulopathy to lessen the “blood clot storm”. The project will use standard in vitro viral infectivity assays and in vivo immune competent tumor-bearing mice models infected with a lethal strain of COVID-19. Together, these studies will demonstrate that the proposed lead survival factor inhibitor can significantly reduce the attachment, entry and replication of COVID-19 virus as well as reduce the immune suppressive nature of infected lung alveolar epithelial cells in vitro and in vivo.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.