Cell protection, immunomodulation and virus inhibition by an endogenous substance

The endogenous molecule itaconic acid has antiviral and anti-inflammatory effects, researchers at TWINCORE recently demonstrated. In collaboration with scientists from the Helmholtz Center 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 acid 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, Center for Experimental and Clinical Infection Research in Hanover. All three substances occur naturally in higher organisms, and Pessler’s research group had first discovered all three in lymph nodes and the spleen, important organs of the immune systemin 2021. “We then further characterized these isomers. Here the results with citraconic acid were most promising for drug development,” explains Pessler.

The researchers discovered that citraconic acid has several positive effects on the immune system at the same time. “We found that citraconic acid activates an important signaling pathway in the immune system,” Pessler says. “The so-called NRF2 pathway regulates antioxidant 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 saw a strong inhibition of messenger substances that cause inflammation. “It inhibits the signaling cascades of type 1 interferons, reducing pro-inflammatory cytokines and chemokines,” Pessler says. “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 influenza viruses. They found that citraconic acid, in particular, almost completely suppressed the release of virus particles from infected cells. Citraconic acid was also stronger in this area than itaconic acid and mesaconic acid. Through this simultaneous inhibition of viral replication, messengers and cell-damaging oxidizing molecules, Pessler hopes that citraconic acid-based drugs will help patients with severe viral infections such as flu, but also COVID-19. Such inhibitors could find clinically important applications.

Pessler and his team thought so too: itaconic acid and citraconic acid interact directly. The mitochondrial enzyme ACOD1 plays a central role in this. 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,” said Dr. Fangfang Chen. The biotechnologist did most of the experimental work in the context of her dissertation. “Too much itaconic acid can weaken the immune system. Therefore, administration of citraconic acid can lead to an increase in immune system performance. This can 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,” Pessler says. Again, citraconic acid could prevent the formation of itaconic acid. Pessler notes, “ACOD1 inhibitors based on citraconic acid could therefore represent a new class of 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 to do before we know if and how best to use citraconic acid-based drugs.”

Provided by TWINCORE – Zentrum für Experimentelle und Klinische Infektionsforschung