Novel Nucleoside Analogues to Combat Emerging Diseases

Thu, 28 May 2026 00:00:00 +0000

Introduction and Clinical Need

Viral diseases are an ever-present threat to public health, a reality the COVID-19 pandemic made painfully clear. While effective antiviral treatments exist for chronic diseases like HIV and hepatitis, many respiratory infections and neglected tropical diseases still have no systematic therapy available.

Mechanism and Challenges of Nucleoside Analogues

Nucleoside analogues (NAs) are synthetic mimics of the natural building blocks of our genome. Viruses rely on these building blocks to replicate, so introducing slightly modified versions can effectively halt viral reproduction. This strategy has been used successfully for years in HIV treatment. However, since our own cells also depend on these same building blocks, an ideal NA must be tolerated by the virus (to block replication) but rejected by human cells (to avoid toxicity).

Designing such nucleoside analogues thus requires careful planning. Most modern NAs use ribose as their central scaffold, a highly constrained structure with a defined shape. Even a small modification in the core can significantly alter its conformation, often resulting in inactive molecules. That is where our project begins.

The Carbobicyclic Scaffold Approach

Carbobicyclic nucleoside analogues (CNAs) are a special class of these modified building blocks. Instead of using ribose as the central scaffold, they replace the oxygen atom in the sugar ring with a carbon atom and lock the structure into a fixed bicyclic shape. This seemingly small change makes the analogue much more stable against enzymatic breakdown in the body. More importantly, the rigid bicyclic scaffold forces the molecule into a specific conformation that may still be recognized by viral enzymes but rejected by human cells. In other words, carbobicyclic analogues can be designed to fool the virus without harming our own metabolism, making them promising candidates for future antiviral drug development.

Initial Design and Preliminary Evaluation

Based on the research from Tony Shing et al., we prepared our first CNA in 2023. In this research, we designed and built a new class of nucleoside analogues with a carbobicyclic core, specifically a bicyclo[4.3.0]nonene structure. Instead of using the natural ribose sugar, we replaced it with a rigid, carbon-based scaffold that locks the molecule into a shape very similar to that of natural nucleosides. This is important because the right shape determines whether a drug works or not.

Using a synthetic strategy built around a Diels–Alder reaction, we were able to produce these analogues in relatively few steps. Some of the analogues from the pilot study inhibited respiratory syncytial virus (RSV) up to 16 times more effectively than their parental ribose-type compound, while showing almost no toxicity to human cells.

Library Expansion and Broad-Spectrum Screening

Following up on these promising results, we further investigated the antiviral potential of our carbobicyclic scaffold. This time, we built a much larger library of analogues and screened them against a broad panel of viruses, including influenza, HCV, HSV, and Zika.

The uracil analogue emerged as a standout candidate. It disrupted the influenza A virus polymerase directly, as confirmed by minigenome assays and supported by computer modeling. Importantly, we also showed that the congested secondary alcohol at the pseudo-C5’ position is still recognized by cellular enzymes and readily converted into the active triphosphate form, without the need for prodrug strategies. Moreover, these triphosphates did not inhibit human DNA or RNA polymerases, suggesting a low risk of off-target toxicity.

Conclusion

We introduced a new class of nucleoside analogues built around a carbobicyclic core that mimics the shape of natural ribose. Using a short and efficient synthetic route, we produced a library of these analogues and identified several promising candidates.

Literature

Tony K. M. Shing, Anthony W. H. Wong, Huiyan Li, Z. F. Liu and Paul K. S. Chan Org. Biomol. Chem., 2014,12, 9439-9445.

Stephan Scheeff, Yan Wang, Mao-Yun Lyu, Behzad Nasiri Ahmadabadi, Sam Chun Kit Hau, Tony K C Hui, Yufeng Zhang, Zhong Zuo, Renee Wan Yi Chan, Billy Wai-Lung Ng, Org. Lett. 2023, 25, 50, 9002–9007.

Stephan Scheeff, Joan Marie Javillo Baguio, Benny Zhibin Liang , Josefina Xeque Amada, Kin Pong Tao, Steven De Jonghe, Leentje Persoons, Tiffany Hoi-Yee Chow, Carmen Ka Man Tse, Roy Yukang Wu, Xinzhou Xu, Zhong Zuo, Peter Pak-Hang Cheung, Renee Wan Yi Chan, Billy Wai-Lung Ng J. Med. Chem. 2026, 69, 5, 5501–5539.

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