AVITHRAPID scientists uncover how a repurposed antibiotic disrupts the core of the coronavirus replication machinery – opening new doors for broad-spectrum antiviral development.
A Strategic Target: The Viral Protease 3CLpro
SARS-CoV-2, the virus behind COVID-19, uses a specific enzyme, the 3C-like protease (3CLpro), to process its polyproteins. After infecting a cell, the virus synthesizes large protein chains that must be cut into smaller, functional pieces. This cutting task is performed by 3CLpro, a molecular scissor that is absolutely essential for viral replication. Without this function, the virus cannot reproduce. This makes 3CLpro one of the most promising targets for antiviral drugs. Medicines like Paxlovid work by inhibiting this enzyme, preventing the virus from completing its replication cycle. What makes 3CLpro even more interesting is that it is highly conserved among coronaviruses, meaning that drugs targeting this enzyme could be effective not only against SARS-CoV-2, but also other existing and future coronaviruses.
Halicin: A Drug with Many Lives
Halicin is not a traditional antiviral. In fact, it was first studied as a treatment for diabetes but failed in clinical development. Years later, it was rediscovered through artificial intelligence as a powerful antibiotic capable of killing multi-drug-resistant bacteria. Halicin works in a novel way by disrupting how bacteria maintain internal energy balance. Because of this, it bypasses many traditional resistance mechanisms. But halicin’s story didn’t stop there. Its unique chemical structure, particularly its reactivity with cysteine residues, has now attracted the attention of antiviral researchers. Could halicin, originally an AI-discovered antibiotic, also inhibit viral proteins?
AVITHRAPID’s Discovery: Dual Binding to 3CLpro
In a recent study published in the International Journal of Biological Macromolecules, AVITHRAPID scientists investigated halicin’s effect on the SARS-CoV-2 3CLpro enzyme. What they found was surprising and highly promising: halicin binds not just to the enzyme’s catalytic site, but also to a second, previously underappreciated site. Mass spectrometry and crystallography showed that halicin covalently attaches to Cys145, the critical residue in the enzyme’s active site. This kind of binding directly blocks the protease’s ability to process viral proteins. But more interestingly, halicin also binds to another cysteine: Cys44. To test how important Cys44 is, the researchers created a mutant version of 3CLpro, replacing Cys44 with alanine. The results were clear. This mutation significantly weakened the enzyme’s stability and reduced its ability to function. Further thermal stability assays confirmed that removing or modifying Cys44 disrupts the structural integrity of the entire protease. This means halicin is working in two ways: it directly inhibits the protease’s cutting function and simultaneously destabilizes the enzyme’s structure. It’s a dual-action mechanism that could make drug resistance more difficult and inhibition more effective.
Implications for Future Antiviral Strategies
The AVITHRAPID findings suggest that halicin – and potentially other molecules with similar reactivity – could be developed into broad-spectrum antivirals. By targeting multiple sites on a viral enzyme, especially those important for structure and function, drugs can become more robust and less vulnerable to resistance mutations. Importantly, halicin was not designed to be an antiviral. Its discovery as a 3CLpro inhibitor underscores the value of drug repurposing – one of the core goals of the AVITHRAPID initiative. Identifying hidden potential in known compounds can dramatically shorten development timelines in a health emergency. In addition, since 3CLpro is highly conserved across coronaviruses, halicin-like inhibitors may provide protection against future coronavirus outbreaks, making them valuable tools for pandemic preparedness.
AVITHRAPID’s Role in Accelerating Antiviral Innovation
AVITHRAPID is a European project dedicated to discovering and advancing broad-spectrum antiviral candidates through smart repurposing and high-throughput technologies. The halicin study exemplifies this mission by showing how computational prediction, structural biology, and biochemical testing can come together to reveal new therapeutic strategies. By exploring molecules that affect multiple viral mechanisms simultaneously, AVITHRAPID contributes not just to fighting current diseases, but to building resilience against future viral threats. The identification of Cys44 as a novel vulnerability in the viral protease adds a valuable new piece to the antiviral research puzzle.
Conclusion
Halicin’s dual targeting of 3CLpro represents a breakthrough in understanding how repurposed drugs can be used to combat viruses in ways not previously imagined. The research by AVITHRAPID scientists not only validates the approach of multi-target inhibition, but also brings attention to new structural weak points in the viral machinery.
In a world where speed, scalability, and scientific creativity are crucial for pandemic response, discoveries like this shine a light on how strategic science can lead the way.
