2. Academic Validation
  3. Harringtonine: A more effective antagonist for Omicron variant

Harringtonine: A more effective antagonist for Omicron variant

  • Biochem Pharmacol. 2023 May 19;115617. doi: 10.1016/j.bcp.2023.115617.
Shiling Hu 1,  Nan Wang 1,  Shaohong Chen 2,  Huajun Zhang 3,  Cheng Wang 1,  Weina Ma 1,  Xinghai Zhang 3,  Yan Wu 3,  Yanni Lv 1,  Zhuoyin Xue 1,  Haoyun Bai 1,  Shuai Ge 1,  Huaizhen He 1,  Wen Lu 1,  Tao Zhang 1,  Yuanyuan Ding 1,  Rui Liu 1,  Shengli Han 1,  Yingzhuan Zhan 1,  Guanqun Zhan 1,  Zengjun Guo 1,  Yongjing Zhang 1,  Jiayu Lu 1,  Jiapan Gao 1,  Qianqian Jia 1,  Yuejin Wang 1,  Hongliang Wang 4,  Shemin Lu 5,  Tengchuan Jin 6,  Sandra Chiu 7,  Langchong He 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
  • 2 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
  • 4 Department of pathogen biology and immunology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
  • 5 School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
  • 6 Division of Life Sciences and Medicine, University of Sciences and Technology of China, Hefei, China.
  • 7 Division of Life Sciences and Medicine, University of Sciences and Technology of China, Hefei, China. Electronic address: [email protected].
  • 8 School of Pharmacy, Xi'an Jiaotong University, Xi'an, China. Electronic address: [email protected].
PMID: 37211174 DOI: 10.1016/j.bcp.2023.115617
Abstract

Fusion with host cell membrane is the main mechanism of Infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we propose that a new strategy to screen small-molecule antagonists blocking SARS-CoV-2 membrane fusion. Using cell membrane chromatography (CMC), we found that harringtonine (HT) simultaneously targeted SARS-CoV-2 S Protein and host cell surface TMPRSS2 expressed by the host cell, and subsequently confirmed that HT can inhibit membrane fusion. HT effectively blocked SARS-CoV-2 original strain entry with the IC50 of 0.217 μM, while the IC50 in delta variant decreased to 0.101 μM, the IC50 in Omicron BA.1 variant was 0.042 μM. Due to high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, however, against BA.5, HT showed a surprising effectiveness. The IC50 in Omicron BA.5 was even lower than 0.0019 μM. The above results revealed the effect of HT on Omicron is very significant. In summary, we characterize HT as a small-molecule antagonist by direct targeting on the Spike protein and TMPRSS2.

Keywords

Omicron variant; SARS-CoV-2; Spike protein; harringtonine; membrane fusion.

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