A high-throughput macrodomain assay to identify coronavirus drugs

In the search for a rapid, easy way to identify drugs to fight SARS-CoV-2, researchers from across the US came together to develop and apply a high-throughput ADP-ribosylhydrolase assay, ADPr-Glo. Here, Dr Veronica Busa and Dr Anthony Leung from Johns Hopkins University describe the ADPr-Glo assay and how it can be leveraged to reveal drug candidates that inhibit viruses – both current and future.

Viruses must invade host cells and hijack the local machinery to replicate their own genome. To further this objective, viruses have developed diverse mechanisms that inactivate and evade the immune systems of their hosts. A common goal of antiviral drugs is to thwart viral replication by inhibiting the viral polymerases or proteases necessary to process viral proteins. Our team pursues a class of drugs that blocks coronavirus replication by targeting a different viral protein.1 This protein is not only critical for viral replication but is also required for full repression of the interferon response during infection. Therefore, besides blocking viral replication, inhibition of this protein may additionally restore the host interferon response against viruses, contributing to recovery from disease.

The COVID-19 pandemic exposed medicine’s need for new classes of drugs to protect against highly contagious and deadly viruses. Although all previously identified coronaviruses are simply contributors to the common cold, three coronaviruses have caused epidemics within the last two decades: SARS-CoV, MERS-CoV and SARS-CoV-2. With hundreds of coronaviruses circulating in wild animals, it is inevitable that there will be another zoonotic transmission of a coronavirus into humans and we must prepare ourselves against this potential future pandemic. Another virus group with pandemic potential is alphaviruses, which includes chikungunya, Mayaro and Eastern Equine Encephalitis. Alphaviruses are mosquito-borne and have been expanding into new regions due to climate change and urbanisation. The US National Institute of Health (NIH) has deemed both coronaviruses and alphaviruses as having pandemic potential,2 but there are only a few coronavirus antivirals on the market and no available treatments for alphaviruses.