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<p>Negative-stranded segmented RNA viruses (NSVs) employ a cap-snatching mechanism for transcription, which makes cap-dependent endonuclease (CEN) an attractive target for drug development. Pathogenic arenaviruses pose a serious threat to humans, yet no approved treatments exist, underscoring the importance of discovering novel compounds targeting arenaviral CENs. Therefore, this study aimed to identify novel CEN inhibitors for arenaviruses and investigate their antiviral mechanisms. A high-throughput screening system based on enzymatic activity of CEN was established for discovering inhibitors of lymphocytic choriomeningitis virus (LCMV). Several hit compounds were screened from a vast natural product library, and then evaluated for both toxicity and inhibition through cellular and animal experiments. One candidate compound was finally identified, and its mechanism of action on CEN was elucidated through simulation analysis and biochemical studies. Moreover, its broad-spectrum effects were investigated among pathogenic arenaviruses as well as representative NSVs. Consequently, salvianolic acid A (SAA) from <i>Salvia miltiorrhiza</i> was identified as a promising compound that effectively inhibited LCMV infection and significantly reduced the viral load via intravenous administration. It was shown to bind to the active pocket of arenaviral CENs while chelating their metal ions through its acid carboxyl group, acting in a substrate-competitive manner. Additionally, SAA exhibited broad-spectrum inhibition of pathogenic arenaviruses as well as representative viruses from the order <i>Bunyavirales</i>. This study identified SAA as a novel CEN inhibitor, particularly for pathogenic arenaviruses, showcasing its promise for antiviral drug development.</p>

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Salvianolic acid A from Salvia miltiorrhiza identified as a cap-dependent endonuclease inhibitor for pathogenic arenaviruses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月3日

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  • Xiao Gao,
  • Yan Wu,
  • Xiao-xue He,
  • Guo-long Liu,
  • Hai-xia Yang,
  • Jia Lu,
  • Xue-rui Zhu,
  • Xin-lan Chen,
  • Chen-shu Zhao,
  • Hao-yu Li,
  • Zhong-fa Zhang,
  • Chan Yang,
  • Shu Shen,
  • Fei Deng,
  • Wei Xu,
  • Shu-wen Liu,
  • Geng-fu Xiao,
  • Xiao-yan Pan

摘要

Negative-stranded segmented RNA viruses (NSVs) employ a cap-snatching mechanism for transcription, which makes cap-dependent endonuclease (CEN) an attractive target for drug development. Pathogenic arenaviruses pose a serious threat to humans, yet no approved treatments exist, underscoring the importance of discovering novel compounds targeting arenaviral CENs. Therefore, this study aimed to identify novel CEN inhibitors for arenaviruses and investigate their antiviral mechanisms. A high-throughput screening system based on enzymatic activity of CEN was established for discovering inhibitors of lymphocytic choriomeningitis virus (LCMV). Several hit compounds were screened from a vast natural product library, and then evaluated for both toxicity and inhibition through cellular and animal experiments. One candidate compound was finally identified, and its mechanism of action on CEN was elucidated through simulation analysis and biochemical studies. Moreover, its broad-spectrum effects were investigated among pathogenic arenaviruses as well as representative NSVs. Consequently, salvianolic acid A (SAA) from Salvia miltiorrhiza was identified as a promising compound that effectively inhibited LCMV infection and significantly reduced the viral load via intravenous administration. It was shown to bind to the active pocket of arenaviral CENs while chelating their metal ions through its acid carboxyl group, acting in a substrate-competitive manner. Additionally, SAA exhibited broad-spectrum inhibition of pathogenic arenaviruses as well as representative viruses from the order Bunyavirales. This study identified SAA as a novel CEN inhibitor, particularly for pathogenic arenaviruses, showcasing its promise for antiviral drug development.