Cell protection, immunomodulation and virus inhibition by an endogenous substance

The endogenous molecule itaconic acid has antiviral and anti-inflammatory effects, as researchers from TWINCORE have recently shown. In cooperation with scientists from the Helmholtz Centre for Infection Research in Braunschweig and the Helmholtz Institute for Pharmaceutical Research Saarland, they have now investigated the closely related substance citraconic acid. The result: Citraconic acid protects cells through antioxidant and anti-inflammatory properties. It also inhibits the release of flu viruses from human cells. They published these results in the journal Nature Metabolism.

“Itaconic acid has two isomers, natural relatives that differ only slightly in chemical structure, mesaconic and citraconic acid,” says PD Dr. Frank Pessler, head of the working group “Biomarkers for Infectious Diseases” at the Institute for Experimental Infection Research at TWINCORE, Centre for Experimental and Clinical Infection Research in Hannover. All three substances occur naturally in higher organisms, and Pessler’s research group had first detected all three in lymph nodes and the spleen, important organs of the immune system, in 2021. “We then characterized these isomers further. Here, the results with citraconic acid were the most promising for drug development,” Pessler explains.

The researchers found that citraconic acid has several positive effects for the immune system at once. “We discovered that citraconic acid activates an important signaling pathway in the immune system,” says Pessler. “The so-called NRF2 pathway controls anti-oxidative and anti-inflammatory processes that can protect cells from harmful influences.” The effect of citraconic acid here is many times stronger than that of itaconic and mesaconic acid.

When the researchers infected human cells with flu viruses and simultaneously treated them with citraconic acid, they observed a strong inhibition of messenger substances that trigger inflammation. “It inhibits the signaling cascades of type 1 interferons, thereby reducing proinflammatory cytokines and chemokines,” says Pessler. “These are signaling molecules that initiate and amplify processes in the immune system.”

In the same experiments, the researchers also tested the effect of the three isomers on the replication of flu viruses. They found that citraconic acid in particular nearly completely suppressed the release of virus particles from infected cells. Citraconic acid was also stronger than itaconic and mesaconic acid in this area. Through this simultaneous inhibition of viral replication, messenger substances and cell-damaging oxidizing molecules, Pessler hopes that drugs based on citraconic acid will help patients with severe viral infections such as influenza, but also COVID-19. Such inhibitors could find clinically important applications.

Pessler and his team also found that itaconic acid and citraconic acid interact directly. Here, the mitochondrial enzyme ACOD1 plays a central role. ACOD1 mediates the synthesis of itaconic acid in inflamed tissues.

“Citraconic acid prevents the production of itaconic acid by binding directly to the active site of the enzyme. Such inhibitors were previously unknown,” says Dr. Fangfang Chen. The biotechnologist did most of the experimental work as part of her doctoral thesis. “Too much itaconic acid can weaken the immune system. Therefore, the administration of citraconic acid could lead to an increase in the performance of the immune system. This could help with advanced sepsis, or blood poisoning, or in people whose immune systems respond poorly to vaccinations,” she notes.

“Other research groups have shown that itaconic acid can promote the growth of certain tumors,” says Pessler. Again, citraconic acid could prevent the formation of itaconic acid. Pessler observes, “ACOD1 inhibitors based on citraconic acid could therefore form a new class of anti-cancer drugs.”

“We have already applied for a patent for medical applications of citraconic acid,” concludes Pessler. “However, we still have a lot of work ahead of us before we know whether and how drugs based on citraconic acid can best be used.”

Provided by
TWINCORE – Zentrum für Experimentelle und Klinische Infektionsforschung