The research demonstrates that the coronavirus enzyme PLpro physically interacts with the receptor MDA5 and inhibits the ISGylation process.
Research has found a coronavirus enzyme called papain-like protease (PLpro) blocks the body's immune response to COVID-19 infection. This suggests that therapies that target and inhibit the enzyme may help to treat COVID-19.
"SARS-CoV-2–the virus that causes COVID-19–has evolved quickly against many of the body's well-known defense mechanisms," said Michaela Gack, PhD, scientific director of the Cleveland Clinic’s Florida Research and Innovation Center, in a press release. "Our findings, however, 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. We discovered that inhibiting PLpro may help rescue the early immune response that is key to limiting viral replication and spread."
One of the body's frontline immune defenses is a class of receptor proteins, including one called MDA5, that identify invaders by foreign patterns in their genetic material. When a foreign pattern is recognized, these receptors become activated and kick-start the antiviral immune system. This is done in part by increasing the downstream expression of proteins encoded by interferon-stimulated genes (ISGs).
Gack and her team identified a novel mechanism that leads to MDA5 activation during virus infection, finding 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. The research demonstrates that the coronavirus enzyme PLpro physically interacts with the receptor MDA5 and inhibits the ISGylation process.
"We're already looking forward to the next phase of study to investigate whether blocking PLpro's enzymatic function, or its interaction with MDA5, will help strengthen the human immune response against the virus," Gack said in the press release. "If so, PLpro would certainly be an attractive target for future anti-COVID-19 therapeutics."
New study points to novel drug target for treating COVID-19 [news release]. EurekAlert; March 16, 2021. Accessed March 19, 2021. https://www.eurekalert.org/pub_releases/2021-03/cc-nsp031621.php