Antiviral Profiling and Cellular Activation of Carbobicyclic Nucleoside Analogues

  • J Med Chem. 2026 Mar 12;69(5):5501-5539. doi: 10.1021/acs.jmedchem.5c02584.
Stephan Scheeff  1 ,  Joan Marie Javillo Baguio  2  3 ,  Benny Zhibin Liang  4  5 ,  Josefina Xeque Amada  1 ,  Kin Pong Tao  2  3 ,  Steven De Jonghe  6 ,  Leentje Persoons  7 ,  Tiffany Hoi-Yee Chow  1 ,  Carmen Ka Man Tse  4  5 ,  Roy Yukang Wu  1 ,  Xinzhou Xu  4  5 ,  Zhong Zuo  1 ,  Peter Pak-Hang Cheung  4  5 ,  Renee Wan Yi Chan  2  5  3 ,  Billy Wai-Lung Ng  1  5  3  8
Affiliations
  • 1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 2. Department of Paediatrics, Faculty of Medicine; S.H. Ho Research Centre for Infectious Diseases, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 3. CUHK-Hub of Obstetric and Paediatric Excellence; The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 4. Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 5. Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
  • 6. KU Leuven,Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Molecular, Structural and Translational Virology Research Group, Herestraat 49, box 1049, 3000 Leuven, Belgium.
  • 7. KU Leuven,Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, Molecular Genetics and Therapeutics in Virology and Oncology Research Group, Herestraat 49, box 1048, 3000 Leuven, Belgium.
  • 8. Gerald Choa Neuroscience Institute, The Chinese University of Hong Kong, Shatin, Hong Kong.
PMID: 41714882 DOI: 10.1021/acs.jmedchem.5c02584
Abstract

Nucleoside analogues are important Antiviral and Anticancer agents. In this study, we investigated a new class of nucleoside analogues built on a synthetically accessible carbobicyclic scaffold designed as a conformational mimic of ribose. Antiviral screening of our library revealed pan-antiviral activity against a range of viruses, including HCV, HSV, and influenza. Structure-activity relationship (SAR) studies highlighted the critical role of the carbocyclic scaffold. The uracil analogue 2a inhibited influenza A virus replication through direct disruption of the viral polymerase, as confirmed by a minigenome assay and further supported by in silico modeling. Importantly, metabolism studies demonstrated that congested C5'-OH is readily phosphorylated without the need for prodrug formulations. The resulting triphosphate metabolites are not substrates of human DNA/RNA polymerases, a primary mechanism of nucleoside drug toxicity. Supported by comprehensive synthetic schemes, we present a carbobicyclic scaffold with altered architecture as a promising chemotype for developing novel nucleoside therapeutics.

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