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.
