An adenosine analog shows high antiviral potency against coronavirus and arenavirus mainly through an unusual base pairing mode

  • Nat Commun. 2024 Dec 30;15(1):10750. doi: 10.1038/s41467-024-54918-3.
Xiaoying Jia  #  1 ,  Xuping Jing  #  1 ,  Ming Li  #  2 ,  Minli Gao  #  3 ,  Yao Zhong  #  1  4 ,  Entao Li  #  2  5 ,  Yang Liu  1 ,  Rui Li  1 ,  Guoqiang Yao  3 ,  Qiaojie Liu  1 ,  Minmin Zhou  1  4 ,  Yuxia Hou  1  4 ,  Linfeng An  2 ,  Yibao Hong  2 ,  Shanshan Li  2 ,  Jiancun Zhang  6 ,  Wei Wang  7 ,  Kaiming Zhang  8  9  10 ,  Peng Gong  11  12 ,  Sandra Chiu  13  14  15
Affiliations
  • 1. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei, China.
  • 2. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3. State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 4. University of Chinese Academy of Sciences, Beijing, China.
  • 5. Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 6. State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China. [email protected].
  • 7. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei, China. [email protected].
  • 8. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 9. MOE Key Laboratory for Cellular Dynamics and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, China. [email protected].
  • 10. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, China. [email protected].
  • 11. Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, No. 262 Jin Long Street, Wuhan, Hubei, China. [email protected].
  • 12. Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin, China. [email protected].
  • 13. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 14. Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 15. Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, China. [email protected].
  • # Contributed equally.
PMID: 39737930 DOI: 10.1038/s41467-024-54918-3
Abstract

By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in Antiviral therapy for RNA virus-related diseases. However, most ribose-modified NAs do not present broad-spectrum features, likely due to differences in ribose-RdRP interactions across virus families. Here, we show that HNC-1664, an adenosine analog with modifications both in ribose and base, has broad-spectrum Antiviral activity against positive-strand coronaviruses and negative-strand arenaviruses. Importantly, treatment with HNC-1664 demonstrate anti-SARS-CoV-2 efficacy in infected K18-human ACE2 mice, with reduced viral titer and mortality, as well as improved lung injury. Enzymology data demonstrate that HNC-1664 inhibits RNA synthesis mainly at the pre-catalysis stage. The cryo-EM structures of HNC-1664-bound RdRP-RNA complexes from both SARS-CoV-2 and LASV reveal an unusual base pairing mode of HNC-1664 in part due to its base modification, thus revealing its great potency in binding but not catalysis. Under certain circumstances, 1664-TP can be slowly incorporated by RdRP through regular Watson-Crick base pairing, as evidenced by enzymology data and an HNC-1664-incorporated crystal structure of the RdRP-RNA complex. Overall, HNC-1664 achieves broad-spectrum characteristics by favoring an alternative base pairing strategy to non-catalytically block RNA synthesis, providing a novel concept for the rational development of NA drugs.

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