At the Hebrew University of Jerusalem, researchers have found a surprising new way to fight the flu—with help from a compound found in chocolate.

Their study, published in Proceedings of the National Academy of Sciences, reveals a drug combination that performs better than current treatments, including Tamiflu, especially against drug-resistant strains.

“We’re not just offering a better flu drug,” said Prof. Isaiah Arkin, the study’s lead author. “We’re introducing a new way to target viruses—one that may help us prepare for future pandemics.”

The treatment pairs theobromine, a molecule found in chocolate, with a lesser-known compound called arainosine.

Outsmarting an Evolving Virus With A Bit of Help From Chocolate

Each year, influenza sweeps across the globe, sickening millions and killing hundreds of thousands. In the United States alone, the economic toll exceeds $87 billion annually. Vaccines help, but they must be updated each season. Antiviral drugs like oseltamivir (better known as Tamiflu) are increasingly ineffective as the virus evolves.

The team at Hebrew University decided to try something different. Rather than chasing the virus’s frequently mutating surface proteins, they set their sights on a structure deep in the viral architecture: the M2 ion channel. This tiny molecular gate helps the virus replicate by shuttling protons across its membrane.

That gate, it turns out, is a weakness—but one that viruses have evolved to protect. Early drugs like amantadine targeted the M2 channel, but resistance developed quickly. Prof. Arkin’s team hoped to find a new compound—or combination of compounds—that could close the gate more effectively, and with less risk of resistance.

To do that, they turned to an unlikely ally: bacteria.

E. coli Joins the Flu Battle

Using genetically engineered bacteria, the team built a high-throughput screening system. The idea was elegant: if the M2 channel worked properly inside the bacteria, it would disrupt their growth. But if a compound blocked the channel, the bacteria would recover.

After running thousands of tests on a library of 2,839 repurposed drugs, they found a few promising candidates. One stood out: theobromine, a compound best known for giving chocolate its bitter edge—and making it dangerous for dogs.

Even more intriguing was what happened when they paired theobromine with arainosine, a breakdown product of an older antiviral called vidarabine. At low doses, neither compound did much on its own. But together, they showed striking synergy. In cell cultures infected with H1N1 swine flu or H5N1 avian flu, the duo stopped the virus cold—even when Tamiflu failed.

“Complete protection from virus-induced cellular death is observed at 10 nanomolar of arainosine with 30 nanomolar of theobromine,” the authors reported.

Outpacing Tamiflu—In Mice

The most dramatic test came in live animals. Mice infected with flu were given different doses of the drug combo. At moderate levels, the treatment slashed the amount of viral RNA in the lungs by over 75%. Higher doses offered diminishing returns—an unexpected quirk that may be linked to the drugs’ chemical interactions.

But the real test came with a lethal strain of influenza known as PR8. In untreated mice, body weight plummeted and symptoms worsened. Mice treated with Tamiflu fared better. But the theobromine-arainosine combo did even more: it cut the viral load more dramatically and nearly halted weight loss.

The study noted there was a 15,717-fold reduction in viral RNA compared to a 3,077-fold drop with Tamiflu.

When the Virus Fights Back

One of the most striking findings was how the virus responded—or didn’t respond—to the new treatment. Resistance has long plagued antiviral drugs. But when the researchers used bacterial genetics to simulate years of potential mutations, they found theobromine was unusually resilient.

“The M2 channel is less likely to develop resistance mutations against theobromine,” the authors wrote. By contrast, classic drugs like rimantadine showed clear pathways to resistance. The new combination may not just be more effective—it might also hold up longer.

The reason likely lies in how the drugs interact with the channel. Theobromine appears to block the narrow entrance. Arainosine binds further down the channel. Together, they jam the gate in a way that the virus struggles to evade.

A Universal Approach to Viral Infections?

Ion channels aren’t unique to influenza. They’re found in many viruses, including coronaviruses. That’s what makes this discovery more than a one-hit wonder.

“The outcome of this study represents a new potential treatment option for influenza alongside an approach that is sufficiently general and readily applicable to other viral targets,” the authors wrote.

For now, the next step is to begin human trials. A university spinout company, ViroBlock, is developing the treatment for broader use. There are hurdles ahead, of course—combination therapies are more complex to develop and regulate. But history offers precedent. Paxlovid, the COVID-19 treatment, also relies on a drug pair.

If these early results hold, a chocolate-derived compound may someday sit at the heart of a new generation of flu treatments.