Researchers from the University of Barcelona, Leiden University (Netherlands) and the University of York and the Francis Crick Institute (United Kingdom) have designed a new family of molecules that inhibit neuraminidase, one of the proteins that coats the influenza virus and a key target in many first-line treatments for both seasonal and pandemic influenza. The new compounds are based on the chemical structure of oseltamivir (Tamiflu), a clinically proven antiviral drug.
The paper, published in an article in Proceedings of the National Academy of Sciences (PNAS), was led by Carme Rovira, an ICREA research professor at the Department of Inorganic and Organic Chemistry at the Faculty of Chemistry and a member of the Institute of Theoretical and Computational Chemistry (IQTCUB) at the University of Barcelona, Gideon J. Davies from the University of York, and Herman S. Overkleeft, from Leiden University.
Complete inactivation of a key protein involved in influenza infection
Neuraminidase (NA) is one of the key surface enzymes of the influenza virus. It helps newly formed virus particles to escape from infected cells and spread. The new study presents a series of compounds - sugar-derived aziridines - that bind strongly to neuraminidase and inhibit its activity during viral infection.
Initially, the new compounds mimic the enzyme's transition state. Subsequently, unlike current flu inhibitors, these compounds completely deactivate the enzyme by forming a chemical bond with a key amino acid in the active site. As well as being potential antivirals, they can also be repurposed to label, visualize and quantify active neuraminidase in complex samples, including seasonal flu vaccines.
In the experimental protocol, the team replaced the alkene in the oseltamivir compound with a configured aziridine ring that can act as a reactive group. This enables the covalent and permanent inhibition of neuraminidase activity, thereby overcoming the reversibility of current drugs against viral infection. In microneutralization assays approved by the World Health Organization (WHO), several N-acyl aziridines demonstrated very strong antiviral effects in cell cultures, with a particularly potent response against influenza A (H3N2) in the study's assays. The compounds are also potent against neuraminidase isolated from strains currently associated with avian influenza (H5N1).
"For me, one of the great strengths of this study is the synergy between the three teams, funded by the European Research Council's (ERC) Synergy grant programme: synthesis, computing, 3D structures and biology come together to deliver a powerful new class of anti-influenza agents," says Professor Gideon J. Davies.
Professor Carme Rovira explains: "Our joint study enabled us to observe how these molecules bind to neuraminidase at the atomic level, first by altering the enzyme's transition state and then by covalently blocking it. It is particularly exciting to see how computational methods are helping to design inhibitors that can also serve as tools for visualizing the virus."
Inhibitory molecules with a unique mechanism of action
This technology provides a means of designing next-generation neuraminidase inhibitors and probes capable of measuring active NA, which are highly useful in research, diagnosis and vaccine quality control. This could enable a faster assessment of neuraminidase content and function in the fight against influenza.
"I am keen to continue developing this technology with a view to clinical application. This will not be easy, as drug development is a long and costly process in which failure is more likely than success. However, the unique mechanism of action of these sugar aziridines, which we are in the process of patenting, gives us a real advantage over other approaches," concludes researcher Herman S. Overkleeft.
Reference article:
Vriends, Merijn B. L. et al. "Oseltamivir aziridines are potent influenza neuraminidase inhibitors and imaging agents" . Proceedings of the National Academy of Sciences, març de 2026. DOI: 10.1073/pnas.2504045123
