Project 465078

The COVID-19 pandemic has underscored the severe threat posed by emerging coronaviruses. In the absence of effective broadly-acting antiviral therapies against coronaviruses, we are vulnerable to coronaviruses that may emerge in future. To address this gap, we aim to develop broadly-acting antivirals that target highly conserved aspects of coronavirus replication. Such antivirals are expected to be active against multiple coronaviruses, including ones that may emerge in future. Cyclophilin inhibitors, which target cellular proteins known as cyclophilins, exhibit broad antiviral activity against many unrelated viruses, including coronaviruses and hepatitis C virus. However, the roles of cyclophilins in coronavirus replication are still unknown. We have shown that treatment with cyclophilin inhibitors enhances cellular defence mechanisms that counteract viral replication. We propose that cyclophilins are required for coronavirus replication, and evasion of antiviral defence mechanisms. In this proposal, we will characterize the role of cyclophilins in coronavirus replication, determine the antiviral mechanisms of cyclophilin inhibitors against coronaviruses, and identify cellular defence mechanisms that are effective in counteracting coronavirus infection. By understanding these mechanisms, we will advance the development of improved cyclophilin inhibitors as broad-spectrum antivirals to prepare for future emerging coronaviruses. In parallel, we will gain insight into the mechanisms that cells use to restrict the replication of coronaviruses. Through these activities, we will pave the way for development of novel antiviral countermeasures against coronaviruses to strengthen pandemic preparedness and mitigate the risks of future emerging coronaviruses.