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| These new molecules can 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.Image Credit:University of Barcelona (NC-ND) |
The Core Concept: Researchers have designed a novel family of antiviral molecules—sugar-derived aziridines based on the structure of oseltamivir (Tamiflu)—that effectively bind to and inhibit neuraminidase, a key surface protein required for the spread of the influenza virus.
Key Distinction/Mechanism: Unlike current first-line flu treatments which act as reversible inhibitors, these new compounds initially mimic the enzyme’s transition state and subsequently form a covalent chemical bond with a key amino acid in the active site. This creates an irreversible block, permanently deactivating the enzyme and halting viral replication.
Major Frameworks/Components:
- Neuraminidase (NA) Targeting: Focusing on the specific viral surface enzyme responsible for enabling newly formed virus particles to detach from and exit infected host cells.
- Aziridine Ring Substitution: The structural modification of replacing the alkene group in standard oseltamivir with a highly configured aziridine ring to act as the primary reactive agent.
- Covalent Inhibition: The chemical mechanism ensuring permanent deactivation of the viral enzyme, overcoming the limitations and reversibility of traditional antiviral drugs.
- Computational Structural Biology: The utilization of atomic-level 3D modeling and computational methods to observe transition states and design the precise molecular structure of the inhibitors.
Branch of Science: Virology, Pharmacology, Biochemistry, and Computational Chemistry.
Future Application: The compounds are foundational for designing next-generation antiviral therapeutics against both seasonal (H3N2) and pandemic (avian H5N1) influenza strains. Additionally, they can be repurposed as laboratory and diagnostic probes to label, visualize, and measure active neuraminidase in complex biological samples and vaccine quality control assays.
Why It Matters: By achieving complete, irreversible inactivation of a primary viral mechanism, this chemical innovation offers a critical advantage over existing flu treatments. It provides a potent new strategy for managing influenza outbreaks while simultaneously supplying the scientific community with advanced imaging tools for viral research and vaccine development.
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| 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. Photo Credit: Courtesy of University of Barcelona |
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.
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 program: 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 applications. 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.
Published in journal: Proceedings of the National Academy of Sciences
Title: Oseltamivir aziridines are potent influenza neuraminidase inhibitors and imaging agents
Authors: Merijn B. L. Vriends, Elisha Moran, Martín Calvelo, Thomas Hansen, Isabelle B. Pickles, Xincheng Xin, Marieke Biezeno, Zachary W. B. Armstrong, Maria J. Ferraz, Lei Li, Alice Lilley, Ruth Harvey, Dmitri V. Filippov, Qinghua Liao, Sybrin P. Schröder, Gijsbert A. van der Marel, Marta Artola, Johannes M. F. G. Aerts, James N. Blaza, Jeroen D. C. Codée, Carme Rovira, Herman S. Overkleeft, and Gideon J. Davies
Source/Credit: University of Barcelona
Reference Number: vi032426_01
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