Study identifies potential drug target for treating COVID-19

Researchers from Cleveland Clinic’s Florida Research and Innovation Center (FRIC), US, have identified a potential new target for anti-COVID-19 therapies. 

The team discovered that a coronavirus enzyme called papain-like protease (PL^pro) blocks the body’s immune response to the infection. According to the researchers, more research is necessary, but the findings suggest that therapeutics that inhibit the enzyme may help treat COVID-19.

“SARS-CoV-2 – the virus that causes COVID-19 – has evolved quickly against many of the body’s well-known defence mechanisms,” said lead researcher Dr Michaela Gack. “Our findings, however, offer insights into a never-before characterised mechanism of immune activation and how PL^pro disrupts this response, enabling SARS-CoV-2 to freely replicate and wreak havoc throughout the host. We discovered that inhibiting PL^pro may help rescue the early immune response that is key to limiting viral replication and spread.”

The researchers say that one of the body’s frontline immune defences is a class of receptor proteins, including one called MDA5, that identify invaders by foreign patterns in their genetic material. When the receptors recognise a foreign pattern, they activate and kick-start the immune system into antiviral mode. This is done in part by increasing the downstream expression of proteins encoded by interferon-stimulated genes (ISGs).

In this study, the team identified a novel mechanism that leads to MDA5 activation during COVID-19 infection. They found that ISG15 must physically bind to specific regions in the MDA5 receptor – a process termed ISGylation – in order for MDA5 to effectively activate and unleash antiviral actors against invaders. They showed that ISGylation helps to promote the formation of larger MDA5 protein complexes, which ultimately results in a more robust immune response against a range of viruses.

“While discovery of a novel mechanism of immune activation is exciting on its own,” Gack said, “we also discovered a bit of bad news, which is that SARS-CoV-2 also understands how the mechanism works, considering it has already developed a strategy to block it.”

The research team shows that the coronavirus enzyme PL^pro physically interacts with the receptor MDA5 and inhibits the ISGylation process.

“We are already looking forward to the next phase of study to investigate whether blocking PL^pro‘s enzymatic function or its interaction with MDA5 will help strengthen the human immune response against the virus,” Gack said. “If so, PL^pro would certainly be an attractive target for future anti-COVID-19 therapeutics.”

The findings were published in Nature Microbiology.