Novel drug target for treating Covid
A team of researchers has identified a potential new target for anti-Covid-19 therapies.
The findings, published in Nature Microbiology, indicated that a coronavirus enzyme called PLpro (papain-like protease) blocks the body’s immune response to the infection.
“Our findings offer insights into a never-before characterized mechanism of immune activation and how PLpro disrupts this response, enabling SARS-CoV-2 to freely replicate and wreak havoc throughout the host,” said researcher Michaela Gack from the University of Chicago in the US.
“We discovered that inhibiting PLpro may help rescue the early immune response that is key to limiting viral replication and spread,” Gack added.
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 become activated 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), the researchers said.
In this study, the team identified a novel mechanism that leads to MDA5 activation during virus 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.
The research team also showed that the coronavirus enzyme PLpro physically interacts with the receptor MDA5 and inhibits the ISGylation process.
The researchers said that more research is necessary, but the findings suggest that therapeutics that inhibit the enzyme may help treat Covid-19.
