SARS-CoV-2 Papain-Like Protease Found to Trigger Gut Inflammation but Natural Compounds Might Stop It
Nikhil Prasad Fact checked by:Thailand Medical News Team Jun 18, 2025 8 months, 1 day, 14 hours ago
Thailand Medical News: Chinese Researchers Reveal a Hidden Cause of COVID-19 Related Gut Problems
A new study by scientists from Southern Medical University and the First Affiliated Hospital of Guangzhou Medical University in China has uncovered a dangerous mechanism used by the SARS-CoV-2 virus that can cause serious inflammation in the intestines. At the center of this discovery is a viral enzyme called papain-like protease (PLpro), which not only helps the virus replicate but also weakens the body’s immune defenses by targeting a key protective protein called ISG15.
The researchers have now shown for the first time that this PLpro enzyme doesn't just help the virus spread but also directly causes inflammation in the gut by interfering with the ISG15 pathway. This
Thailand Medical News report explains how this hidden process could be responsible for the persistent gastrointestinal issues experienced by many COVID-19 patients, including those suffering from Long COVID.
How the Virus Inflames the Gut
The PLpro protein of SARS-CoV-2 has been known to silence the immune system, but this new study found that it also triggers an inflammatory response in colonic epithelial cells—the cells lining the large intestine. When PLpro removes ISG15 from its targets, it sends the body’s internal alarm system into overdrive, leading to swelling, irritation, and pain in the digestive tract. These effects were not only seen in lab-grown human cells but also in live mice, confirming the real-world danger of this viral protein.
Mice injected with PLpro developed significant colon inflammation, mirroring the symptoms many people report after COVID-19 infection—such as diarrhea, cramping, and long-term digestive discomfort. The discovery sheds light on how the virus could damage internal organs even after the initial infection has passed.
Natural Compounds Offer Hope
To counter this inflammation, researchers used high-throughput screening to find molecules that could stop PLpro from binding to ISG15. Out of thousands of natural compounds, two stood out: coptisine sulfate (found in certain Chinese herbs) and (+)-shikonin (derived from the root of the Lithospermum plant). These compounds successfully blocked the harmful interaction between PLpro and ISG15.
Both natural molecules were tested in mice and significantly reduced gut inflammation. Detailed lab tests—including surface plasmon resonance and thermal shift assays—confirmed that these compounds attach tightly to PLpro, preventing it from disrupting the ISG15 pathway. Computer simulations and molecular docking studies further supported how well these compounds fit into PLpro’s structure, essentially disabling its harmful effects.
Promising Step Toward COVID Gut Treatment
The study introduces a new way to look at COVID-19’s impact on the body—not just as a respiratory illness but as one that can disturb the gut and immune system in complex ways. Targeting the PLpro/ISG15 interaction might become a promising strategy to reduce inflammation and prevent long-term complications.
In conclusion, the findings highlight how the SARS-CoV-2 virus can hijack immune processes to cause lasting damage in the digestive system. By identifying two safe and natural compounds capable of b
locking this effect, scientists have paved the way for new treatments that could benefit millions experiencing post-COVID gut symptoms. These discoveries also open the door to further research into how other natural compounds might be used to stop the virus’s hidden tricks and protect the body from chronic inflammation.
The study findings were published in the peer reviewed journal: Journal of Medical Virology
https://onlinelibrary.wiley.com/doi/10.1002/jmv.70448
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