2. Academic Validation
  3. Glycyrrhetinic acid blocks SARS-CoV-2 infection by activating the cGAS-STING signalling pathway

Glycyrrhetinic acid blocks SARS-CoV-2 infection by activating the cGAS-STING signalling pathway

  • Br J Pharmacol. 2024 Jun 23. doi: 10.1111/bph.16473.
Hui Qi 1 2 3,  Qin-Hai Ma 4,  Wei Feng 1 2,  Si-Mian Chen 5,  Cai-Sheng Wu 5,  Yanan Wang 1 2,  Tong-Xing Wang 1 2,  Yun-Long Hou 1 2 3,  Zhen-Hua Jia 1 2
Affiliations

Affiliations

  • 1 Hebei Academy of Integrated Traditional Chinese and Western Medicine, Shijiazhuang, Hebei, China.
  • 2 State Key Laboratory for Innovation and Transformation of Luobing Theory, Shijiazhuang, China.
  • 3 New Drug Evaluation Center, Shijiazhuang Yiling Pharmaceutical Co., Ltd, Shijiazhuang, Hebei, China.
  • 4 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 5 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
PMID: 38922702 DOI: 10.1111/bph.16473
Abstract

Background and purpose: Traditional Chinese medicine (TCM) played an important role in controlling the COVID-19 pandemic, but the scientific basis and its active ingredients are still weakly studied. This study aims to decipher the underlying anti-SARS-CoV-2 mechanisms of glycyrrhetinic acid (GA).

Experimental approach: GA's anti-SARS-CoV-2 effect was verified both in vitro and in vivo. Homogeneous time-resolved fluorescence assays, biolayer interferometry technology, and molecular docking were employed to examine interactions of GA with human stimulator of interferon genes (hSTING). Immunofluorescence staining, western blot, and RT-qPCR were used to investigate nuclear translocation of interferon regulatory factor 3 (IRF3) and levels of STING target genes. Pharmacokinetics of GA was studied in mice.

Key results: GA could directly bind to Ser162 and Tyr240 residues of hSTING, thus up-regulating downstream targets and activation of the STING signalling pathway. Such activation is crucial for limiting the replication of SARS-CoV-2 Omicron in Calu-3 cells and protecting against lung injury induced by SARS-CoV-2 Omicron Infection in K18-ACE2 transgenic mice. Immunofluorescence staining and western blot indicated that GA increased levels of phosphorylated STING, phosphorylated TANK-binding kinase-1, and Cyclic GMP-AMP Synthase (cGAS). Importantly, GA increased nuclear translocation of IRF3. Pharmacokinetic analysis of GA in mice indicated it can be absorbed into circulation and detected in the lung at a stable level.

Conclusion and implications: Activation of the cGAS-STING pathway through the GA-STING-IRF3 axis is essential for the Antiviral activity of GA in mice, providing new insights into the potential translation of GA for treating SARS-CoV-2 in patients.

Keywords

3CL‐pro; ACE2; COVID‐19; cGAS‐STING; glycyrrhetinic acid; molecular docking.

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