Led by Professor Billy Ng, Associate Professor from the School of Pharmacy (front row, middle left); and Professor Renee Chan, Associate Professor from the Department of Paediatrics (front row, middle right), the CU Medicine research team unravels a new antiviral molecular scaffold that can jam ‘‘the viral copying machine’’, preventing viral replication and shedding lights on novel antiviral drug discovery.

Scientists at The Faculty of Medicine at The Chinese University of Hong Kong (CU Medicine) have reported the discovery of a new class of carbobicyclic nucleoside analogues that serve as antiviral molecular scaffolds. It offers a groundbreaking approach to combating the global health threat posed by constantly mutating viruses and the declining efficacy of existing treatments. These core chemical building blocks can prevent viruses from replicating without affecting normal human cells, and can be modified to generate many potential drug candidates.

The breakthrough helps overcome major limitations of traditional antiviral drugs, such as high toxicity, synthetic complexity and restricted applications. It offers a safer, more efficient and more flexible synthetic platform for the development of therapies for multiple acute respiratory viral infections and chronic infections, while suggesting a brand-new approach to drug discovery in response to viral mutations and pandemics.

The work is led by Professor Billy Ng, Associate Professor from the School of Pharmacy; and Professor Renee Chan, Associate Professor from the Department of Paediatrics, both from CU Medicine. The findings have been published in Journal of Medicinal Chemistry.

Jamming the photocopier: a new antiviral strategy by redesigning the molecular scaffold   

Viruses cannot reproduce on their own and must hijack human cells to copy themselves. Some existing antiviral drugs, known as nucleoside analogues, work by mimicking the building blocks used in this copying process. By tricking viral copying enzymes into using these look-alike molecules, these drugs can slow or stop viral replication. These drugs are widely used to treat viral infections such as chronic hepatitis B, HIV and emerging viral diseases.

However, traditional nucleoside scaffolds are inherently complex, which can mean that they are difficult to synthesise and may also affect human enzymes, and cause toxic side effects. The growing challenge of viral mutations underscores the pressing need to overcome the limitations of conventional antiviral drug development.

The team addressed this by redesigning the scaffold itself, replacing the usual sugar-based core with a rigid, carbon-based bicyclic scaffold. Rather than hijacking viral genetic material, the newly developed molecules are designed to bind to the copying enzyme of a virus and stop it from working. The team likens this to jamming a photocopier so that it can no longer operate.

Key advantages of the new scaffold:

• Potentially improved safety: limited unintended interactions with human enzymes,lowering the risks of side effects;
• Faster development: the streamlined synthesis requires fewer than 10 steps, enabling new candidates to be designed and evaluated more quickly; and
• Greater versatility: the scaffold can be readily modified to generate diverse candidates against different viruses and, potentially, emerging variants.

This work sets itself apart from traditional drug development as it goes beyond a single molecule or a single virus. It introduces a new molecular scaffold that can be quickly adapted to generate and test a wide range of drug candidates. This could open new opportunities not only for antiviral research but also for drug discovery more broadly.

Exploring the frontier of drug discovery

Traditional drug discovery often begins by screening large “libraries” of existing compounds for useful activity against a disease target. However, such libraries explore only a small part of the vast chemical space[1] available for the design of new medicines. Expanding that space is essential to discovering the next generation of medicines, as antiviral research cannot rely solely on improving old therapies, it must also keep creating new ways to design the next generation of medicines.

Professor Ng, the co-corresponding author of the study,said: “Drug discovery depends not only on biological insights but also on access to new molecular scaffolds that can explore new chemical space. Chemistry is not just about creating new structures but also about developing new functions. Developing synthetically accessible and biologically functional scaffolds is therefore a major frontier in modern drug discovery.”

The team aims to expand this molecular toolbox to discover better antiviral drug candidates, especially as viruses evolve resistance to existing treatments.

Bridging chemistry and biology for translational medicine

The success of this project highlights the team’s unique ability to bridge the gap between complex chemical synthesis and clinical needs. By combining curiosity-driven chemistry with deep biological insights into how viruses behave, the team is accelerating the journey from laboratory discovery to potential therapeutics.

Professor Chan, another co-corresponding author of the study, commented: “This work shows the power of interdisciplinary collaboration across chemistry, virology, pharmacology and structural biology. By bringing these perspectives together, we have uncovered a promising new platform for antiviral drug discovery.”

This research showcases the significance of creating nature-inspired molecular scaffolds and translating them into new therapeutic opportunities. The team is grateful for support from the Bill & Melinda Gates Foundation and the Innovation and Technology Fund from the Innovation and Technology Commission of the HKSAR Government.