Molecular and cellular studies of novel broad-spectrum natural product antivirals against respiratory viruses of pandemic concern

Emerging human respiratory viruses such as SARS-CoV-2 (COVID-19), influenza A virus (acute respiratory infection), and respiratory syncytial virus or RSV (severe respiratory infection in infants and older adults), have had an enormous impact on human health. The World Health Organization (WHO) has declared SARS-CoV-2 and influenza A viruses to be Public Health Emergencies of International Concern (PHEICs). Coinciding surges "tripledemics" can result in co-infections of increased severity and place enormous strain on hospitals and public health resources. Despite continuing worldwide vaccination campaigns, the recurring appearance of new virus variants is creating a tremendous need for safe and effective therapeutics and prophylactics against SARS-CoV-2, Influenza A, and RSV infection. Our research team has discovered an exciting broadly acting antiviral drug that can block infections in human cells caused by SARS-CoV-2, influenza A, and RSV. The drug, cladoniamide A (CA), is a natural product (NP) discovered at the University of British Columbia that blocks a human protein complex called vacuolar ATPase that helps human viruses get into our cells. NPs such as CA have the advantage of more favorable toxicological profiles, fewer side effects, and a faster approval process in comparison to chemically engineered drugs, great advantages when dealing with a pandemic. In this research proposal, we plan to further improve the pharmaceutical and antiviral properties of CA and develop a new class of nature-based broad-spectrum medicines against SARS-CoV-2, influenza A, and RSV viruses. Overall, our research proposal will provide new insight into the potential of NPs as valuable inspirational starting points for developing desperately needed broad-spectrum antivirals.