2. Academic Validation
  3. An adenosine analog shows high antiviral potency against coronavirus and arenavirus mainly through an unusual base pairing mode

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

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. zhang_jiancun@gibh.ac.cn.
  • 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. wangwei@wh.iov.cn.
  • 8 Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. kmzhang@ustc.edu.cn.
  • 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. kmzhang@ustc.edu.cn.
  • 10 Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, China. kmzhang@ustc.edu.cn.
  • 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. gongpeng@wh.iov.cn.
  • 12 Drug Discovery Center for Infectious Diseases, Nankai University, Tianjin, China. gongpeng@wh.iov.cn.
  • 13 Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. qiux@ustc.edu.cn.
  • 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. qiux@ustc.edu.cn.
  • 15 Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, China. qiux@ustc.edu.cn.
  • # 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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