SBIR Phase II: A Novel Host-Directed Broad-Spectrum Antiviral and Efficient Immunomodulatory Agent Against Coronaviruses: Lead Optimization Studies

The broader impact of this Small Business Innovation Research (SBIR) Phase II project stems from the development of a virus agnostic drug that can control the current coronavirus pandemic and potentially future pandemics caused by yet unknown viruses. Since 2020, research has been chasing COVID-19 and its variants by reformulating vaccines and developing more antibodies and antivirals, but the virus has always been ahead, mutating so fast to make those approaches obsolete. Because COVID-19 is not going away, and because a dysregulated (toxic) immune response is not unique to COVID-19, and because viral threats will not stop at COVID-19, a virus and variant agnostic drug that can stop the virus from multiplying, can fix the toxic immune response, is easy to administer in an outpatient or pandemic setting (oral), and can be given early or late in the infection cycle is imperative to get ahead of viral threats. In addition to the positive effect on pandemic preparedness and decreasing the pressure on healthcare systems, such drug can positively impact the economy by preventing the devastating health effects that COVID-19 has on the cardiovascular (heart) and nervous systems, which have led to disability claims sharply rising among the working age group. The proposed project focuses on the lead optimization of a candidate molecule for oral administration against coronaviruses. SARS-CoV-2 infections cause hyperinflammation and autoimmunity leading to multi-organ damage even with mild infections. The damage is cumulative and repeat infections increase the risk of long COVID. These clinical manifestations are due to persistent/chronic infections and dysregulated immune responses. An ideal treatment would not only suppress viral replication but would also restore the immune system homeostasis and healthy immune response. In Phase I, a molecule was designed, synthesized, and shown to be an efficient immunomodulatory and broad-spectrum antiviral. This molecule targets the host rather than the virus which decreases the chances of resistance and makes it virus/variant agnostic, unlike vaccines and direct-acting antivirals. In Phase II, the technical objectives focus on design, synthesis, and testing of analogs with improved drug-like properties for oral administration. Those analogs will be evaluated against several SARS-CoV-2 variants in-vitro, subjected to in-vitro ADME studies, and assessed for their effect on the production of immune mediators in virus-infected cells. The analog with the best profile will advance to in-vivo studies to test its pharmacokinetic and toxicological properties in mice, as well as its efficacy and immune modulations activity in virus-infected animal rodents. 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.