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

SBIR 第一阶段：Ace2 诱饵作为泛冠状病毒治疗药物 (COVID-19)

• 批准号: 2136508
• 负责人: Gabriel Glenn Gregorio
• 金额: $ 25.6万
• 依托单位: WHITE ROCK THERAPEUTICS
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2136508&HistoricalAwards=false
• 关键词: SBIR; Phase; Ace2; decoy; pan

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.

这个小型企业创新研究第一阶段项目的更广泛的影响/商业潜力是推动了一种对患者友好且具有成本效益的方法来预防和治疗由SARS-CoV-2及其变种引起的新冠肺炎感染。如果不能迅速阻止呼吸道传染病病原体的传播，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。该项目将证明一种喷雾式泛冠状病毒中和剂的可行性，这种中和剂可以直接输送到肺部，作为早期、感染后治疗或预防。一种可吸入疗法比目前批准的需要静脉注射的单抗具有更强的商业潜力，这种药物将更有可能保持对未来变种的效力。新冠肺炎病毒预计将在人类中持续存在，其新的变种将继续出现。因此，这项技术在满足这些正在进行的医疗需求方面可能是至关重要的。这项小型企业创新研究(SBIR)第一阶段项目旨在展示一种可吸入诱骗受体的体内效果，该受体将有效地抑制SARS-CoV-2与其内源性细胞靶点的相互作用，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依赖于病毒刺突三聚体与宿主ACE2受体的结合。诱骗受体方法将使用ACE2受体的重组可溶性版本，该受体将结合并包裹病毒颗粒，竞争与内源性ACE2的尖峰相互作用，从而阻止病毒对接到细胞表面。稳定ACE2蛋白的突变可以使其成为诱饵受体，并在可吸入制剂中具有足够的稳定性，使其能够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的一个潜在的致命弱点，因为SARS-CoV-2或类似的冠状病毒不太可能围绕与这种宿主蛋白相互作用的要求发生变异。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。