COVID-19: SARS-CoV-2 Neutralizing Agents

COVID-19超级大流行仍然受到缺乏疫苗或感染控制措施的困扰

COVID-19 super pandemic is still suffering from the lack of a vaccine or infection control measures and the lack of any treatments against this new virus. One of the unique features of SARS-CoV-2 is that it has an R0=2.2 (the ability of an infected patient to spread the disease) vs R0=1 for SARS-CoV and R0=0.3 for Influenza. Due to this, individuals infected with SARS-CoV-2 remain asymptomatic and yet pass on the virus to family, friends and colleagues at work, thus expanding the COVID-19 cases. Given the impending second wave of the pandemic and the potential of SARS-CoV-2 being a seasonal virus, there is a dire urgent need to develop prophylactic vaccines and/or therapy (PV/T), which can treat the viral infection during the virus expansion in the lung and during oxygen therapy. This proposal addresses the COVID-19 pandemic by developing a PV/T, which will be a unique approach that has not been tested before. This project is inspired by discovery of a special agent, i.e., a nanoscale 10 kDa chitosan, derived using proprietary methods from chitosan used as a common diet supplement [‘generally regarded as safe’ (GRAS) by FDA] , referred to as nanoscale chitosan derivative (NCD). NCD1 and other chemical derivatives were synthesized and tested for their anti-viral activity by neutralizing RNA of viruses, such as HIV, respiratory syncytial virus (RSV) and Coxsackie virus. Thus, in preliminary studies, 5 out of 9 examined showed significant anti-viral (80-90%) effects. Further, molecular docking studies showed that NCD1 can dock to the Spike protein of SARS-CoV-2 virus. Finally, we have developed lung targeted nanomedicine methods to combine NCD1 with remdesivir for improving treatment efficacy and expanding its use for prevention. Based on data at hand, it is hypothesized that NCDs by themselves or in combination with remdesivir will provide an excellent PV/T against COVID-19. To test this hypothesis, it is planned to examine in both prophylactic and therapeutic settings: the antiviral effectiveness of NCDs in vitro lung epithelial cell cultures (aim #1), the effectiveness of select top two NCDs with or without remdesivir in EpiAlveolar 3D co-culture model (MatTek) of the air-blood barrier (aim #2), and efficacy of select NCD with or without remdesivir in in vivo mouse models (aim #3). The results will provide us in identifying one or two NCDs as a single agent or in combination with remdesivir as COVID-19 PV/T regimen(s), which will inhibit SARS-CoV-2 infection. The results of these studies will uniquely contribute to the repertoire of COVID-19 prophylactics and therapeutics and allow us to move towards regulatory approval and future clinical trials. The team is uniquely poised to conduct these studies and has appropriate expertise. The successful completion of the proposed research is expected to lead to obtaining regulatory approval for a clinical trial.