SBIR Phase I: Ace2 decoy as a pan-coronavirus therapeutic (COVID-19)

这项小企业创新研究（SBIR）第一阶段项目的更广泛影响/商业潜力是推进一种对患者友好且具有成本效益的方法，以预防和治疗由SARS-CoV-2及其变体引起的COVID-19感染。如果不能迅速阻止呼吸道传染性病原体的传播，可能会造成毁灭性的全球后果，导致数百万人死亡，并造成巨大的经济负担。该项目将证明一种雾化的泛冠状病毒中和剂的可行性，这种药物可以直接输送到肺部，既可以作为早期治疗，也可以作为感染后治疗，也可以作为预防措施。与目前批准的需要静脉给药的单克隆抗体相比，一种可吸入治疗药物具有更强的商业潜力，而且这种药物更有可能对未来的变种保持效力。预计COVID-19病毒将在人群中持续存在，并将继续出现新的变体。因此，这项技术在解决这些持续的医疗需求方面可能至关重要。这项小企业创新研究（SBIR）一期项目旨在证明一种可吸入诱饵受体的体内功效，该受体可以有效抑制SARS-CoV-2与其内源性细胞靶标的相互作用，从而防止宿主感染。SARS-CoV-2病毒进入呼吸道上皮细胞的机制取决于病毒Spike三聚体与宿主Ace2受体的结合。诱骗受体方法将使用一种重组的可溶性Ace2受体，该受体将结合并包裹在病毒颗粒上，与内源性Ace2竞争Spike相互作用，从而阻止病毒对接到细胞表面。Ace2蛋白的稳定突变可以使其作为诱饵受体，并且在可吸入制剂中具有足够的稳定性，使其可以通过雾化器直接部署到呼吸道。对Ace2受体结合的依赖是冠状病毒潜在的致命弱点，因为SARS-CoV-2或类似的冠状病毒不太可能在与这种宿主蛋白相互作用的要求下发生突变。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/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is the advancement of a patient-friendly and cost-effective way to prevent and treat COVID-19 infection arising from SARS-CoV-2 and its variants. The inability to quickly stop the spread of respiratory infectious pathogens can have devastating global consequences, resulting in millions of deaths and creating an enormous economic burden. This project will prove the viability of an aerosolized pan-coronavirus neutralizing agent that can be delivered directly to the lungs, either as an early-stage, post-infection treatment or as a prophylactic. An inhalable therapeutic has a stronger commercial potential than the currently approved monoclonal antibodies which require intravenous delivery, and this drug will be more likely to retain potency against future variants. The COVID-19 virus is expected to persist in the human population, and novel variants thereof will continue to emerge. Therefore, this technology could be crucial in addressing these ongoing medical needs.This Small Business Innovation Research (SBIR) Phase I project aims to demonstrate in vivo efficacy of an inhalable decoy receptor that would effectively inhibit SARS-CoV-2 interaction with its endogenous cellular target and thus prevent infection of the host. The mechanism of SARS-CoV-2 viral entry into respiratory epithelial cells depends on the binding of viral Spike trimer to the host Ace2 receptor. The decoy receptor approach would use a recombinant soluble version of the Ace2 receptor that would bind and coat the viral particle, competing for Spike interaction with endogenous Ace2 and thus prevent virus docking to the cell surface. Stabilizing mutations in the Ace2 protein could enable it to act as a decoy receptor and also have sufficient stability in an inhalable formulation, allowing it to be deployed directly to the respiratory tract via a nebulizer. The dependence on Ace2 receptor binding is a potential Achilles heel of coronaviruses, as it is unlikely that SARS-CoV-2 or similar coronaviruses can mutate around the requirement to interact with this host protein.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.