Pre-clinical development of a novel class of broad-spectrum natural product antivirals

Emerging human viruses such as SARS-CoV-2 (cause of COVID-19), influenza A virus (acute respiratory infection), and Zika virus (microcephaly and other congenital malformations), have had an enormous impact on human health. The World Health Organization (WHO) has declared these three to be Public Health Emergencies of International Concern (PHEICs). Although vaccines have greatly limited COVID-19 and Influenza-related hospitalizations and deaths, these viruses are continually changing, rendering vaccines less effective over time. What's more, no vaccine is available yet for preventing Zika virus infection. Importantly, no broad-spectrum antiviral drugs are available against these three viruses despite the fact that each virus was declared a PHEIC [influenza A pandemic (2009); Zika virus epidemic (2016); COVID-19 pandemic (2019)]. Our research team has discovered an exciting drug that can block infections in human cells caused by SARS-CoV-2, influenza A, and Zika, which we call a broadly acting antiviral. The drug, called cladoniamide A (CA), is a natural product (NP) discovered in British Columbia that blocks a human protein complex called vacuolar ATPase that helps human viruses get into our cells. NPs as drugs have fewer side effects and a faster approval process than chemically engineered drugs, a great advantage in 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 Zika viruses. We anticipate that this research will further develop cladoniamide A and its derivatives so they can be further tested in clinical trials. In the future, this will lead to new and exciting broad-spectrum possibilities for treating other human viral diseases of global health concern.