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

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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Publication Details

Journal
Nature Communications
Published
2024-12-30
DOI
https://doi.org/10.1038/s41467-024-54918-3
Citations
6
Primary Topic
Viral gastroenteritis research and epidemiology
Type
article
Field-Weighted Citation Impact
2.33

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article

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

Minli Gao, Minmin Zhou, Guoqiang Yao, Sandra Chiu et al.
6 citations
Nature Communications
Viral gastroenteritis research and epidemiology
2.33
article

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

Minli Gao, Minmin Zhou, Guoqiang Yao, Sandra Chiu, Qiaojie Liu, Entao Li, Yao Zhong, Peng Gong, Yaoqin Hong, Xuping Jing, Shanshan Li, Jiancun Zhang, Yuxia Hou, Li An, Ming Li, Yang Liu, Wei Wang, Rui Li, Kaiming Zhang
article en
6 citations

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.

Nature CommunicationsVol. 15(1)
University of Science and Technology of China (CN), Anhui University (CN), Chinese Academy of Sciences (CN), Nankai University (CN), Guangzhou Institutes of Biomedicine and Health (CN), Wuhan Institute of Virology (CN), Anhui Provincial Center for Disease Control and Prevention (CN), State Key Laboratory of Respiratory Disease (CN), University of Chinese Academy of Sciences (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, Natural Science Foundation of Hubei Province, University of Science and Technology of China, Natural Science Foundation of Anhui Province, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities
Good health and well-being
Openalex Percentile: Top 11%
Viral gastroenteritis research and epidemiology
2.33
DOIOpen Access PDFOpenAlex
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