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

Xiaoying Jia, Xuping Jing, Ming Li, Minli Gao, Yao Zhong, Entao Li, Yang Liu, Rui Li, Guoqiang Yao, Qiaojie Liu, Minmin Zhou, Yuxia Hou, Linfeng An, Yibao Hong, Shanshan Li, Jiancun Zhang (), Wei Wang (), Kaiming Zhang (), Peng Gong () and Sandra Chiu ()
Additional contact information
Xiaoying Jia: No. 262 Jin Long Street
Xuping Jing: No. 262 Jin Long Street
Ming Li: University of Science and Technology of China
Minli Gao: Chinese Academy of Sciences
Yao Zhong: No. 262 Jin Long Street
Entao Li: University of Science and Technology of China
Yang Liu: No. 262 Jin Long Street
Rui Li: No. 262 Jin Long Street
Guoqiang Yao: Chinese Academy of Sciences
Qiaojie Liu: No. 262 Jin Long Street
Minmin Zhou: No. 262 Jin Long Street
Yuxia Hou: No. 262 Jin Long Street
Linfeng An: University of Science and Technology of China
Yibao Hong: University of Science and Technology of China
Shanshan Li: University of Science and Technology of China
Jiancun Zhang: Chinese Academy of Sciences
Wei Wang: No. 262 Jin Long Street
Kaiming Zhang: University of Science and Technology of China
Peng Gong: No. 262 Jin Long Street
Sandra Chiu: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54918-3

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