2. Academic Validation
  3. Antiviral Profiling and Cellular Activation of Carbobicyclic Nucleoside Analogues

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

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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