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New Study From Cleveland Clinic Pathogens Researchers Points to Novel Drug Target for Treating COVID-19

Dr. Gack and other FRIC researchers discovered that a coronavirus enzyme blocks the activity of a previously undefined host immune response, suggesting therapeutics that inhibit the enzyme may help treat COVID-19.


Researchers from the newly created Florida Research and Innovation Center (FRIC) have published their first COVID-19 study results. The findings, published in Nature Microbiology, identify a potential new target for anti-COVID-19 therapies.

Led by FRIC scientific director Michaela Gack, PhD, the team uncovered a previously undefined mechanism of innate immunity and how a coronavirus enzyme called PLpro (papain-like protease) disrupts it, ultimately enabling SARS-CoV-2 (the virus that causes COVID-19) to freely replicate and wreak havoc throughout host cells. More research is necessary, but the findings suggest that inhibiting PLpro may help rescue the human immune response and prevent viral replication and spread.

“SARS-CoV-2 has evolved quickly against many well-known host defense mechanisms,” said Dr. Gack. “Our findings, however, offer insights into a never-before characterized immune mechanism. The virus’ ability to evade it further demonstrates just how dynamic and formidable SARS-CoV-2 is.”

ISG15 and MDA5 proteins are critical players in new immune defense mechanism

It is widely accepted that 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 the receptors recognize a foreign pattern, they become activated and kick start the immune system into antiviral mode. This is done in part by increasing, through a series of steps, the downstream expression of proteins encoded by interferon-stimulated genes (ISGs).

Here, Dr. Gack and her team identified a novel mechanism that leads to MDA5 activation during virus infection.

They found that ISG15 must physically bind to specific regions in MDA5 receptors—a process termed ISGylation—in order for MDA5 to effectively activate and unleash antiviral actors against invaders. ISGylation, they showed, helps to promote the formation of larger MDA5 protein complexes, which ultimately results in a more robust immune response against a range of viruses.  

Immune-suppressing coronavirus enzyme may be new target for therapeutic developers

“While discovery of a novel mechanism of immune activation is exciting on its own,” commented Dr. Gack, “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.”

Dr. Gack’s team shows 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. If so, PLpro would certainly be an attractive target for future anti-COVID-19 therapeutics.”

Postdoctoral fellow GuanQun “Leo” Liu, PhD, and project staff Jung-Hyun Lee, PhD, both members of Dr. Gack’s laboratory at the FRIC, are co-first authors on the study, which was supported by the National Institutes of Health. The FRIC, which complements and expands research underway at Lerner Research Institute and Cleveland Clinic Florida’s five regional hospitals—is located in Port St. Lucie, Florida, and is closely integrated with the Global Center for Pathogen Research & Human Health.

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