Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry

Wu, Shuo; Yang, Ge; Wang, Kun; Yan, Haiyan; Wang, Huiqiang; Li, Xingqiong; Qiao, Lijun; Wu, Mengyuan; Wang, Ya; Jiang, Jian-Dong; Li, Yuhuan

doi:10.3390/ijms26136334

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Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry

by

Shuo Wu

^1,2,†,

Ge Yang

^1,†,

Kun Wang

¹,

Haiyan Yan

¹,

Huiqiang Wang

¹,

Xingqiong Li

¹,

Lijun Qiao

¹,

Mengyuan Wu

¹,

Ya Wang

¹,

Jian-Dong Jiang

^1,2,* and

Yuhuan Li

^1,2,*

¹

CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development, NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

²

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

^*

Authors to whom correspondence should be addressed.

^†

Those authors contributed equally to this work

Int. J. Mol. Sci. 2025, 26(13), 6334; https://doi.org/10.3390/ijms26136334

Submission received: 21 May 2025 / Revised: 21 June 2025 / Accepted: 26 June 2025 / Published: 30 June 2025

(This article belongs to the Section Molecular Microbiology)

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Abstract

Glycyrrhizic acid (GA) and its derivatives have been reported to have potent pharmacological effects against viral infections, including SARS-CoV and SARS-CoV-2. However, their antiviral mechanisms against coronaviruses are not fully understood. In this study, we found that diammonium glycyrrhizinate (DG) can effectively reduce infections of several human coronaviruses, including HCoV-OC43, HCoV-229E, and SARS-CoV-2, as well as newly emerged variants, with EC₅₀ values ranging from 115 to 391 μg/mL being recorded. Time-of-addition and pseudotype virus infection studies indicated that DG treatment dramatically inhibits the process of virus entry into cells. Furthermore, we demonstrated that DG broadly binds to the RBD of human coronaviruses, thereby blocking spike-mediated cellular entry, by using TR-FRET-based receptor-binding domain (RBD)-ACE2 interaction assay, capillary electrophoresis (CE), and surface plasmon resonance (SPR) assay. In support of this notion, studies of molecular docking and amino acid mutation showed that DG may directly bind to a conserved hydrophobic pocket of the RBD of coronaviruses. Importantly, intranasal administration of DG had a significant protective effect against viral infection in a HCoV-OC43 mouse model. Finally, we found that combinations of DG and other coronavirus inhibitors exhibited antiviral synergy. In summary, our studies strongly reveal that DG exerts broad-spectrum antiviral activity against human coronaviruses by interrupting spike-mediated cellular entry, demonstrating the pharmacological feasibility of using DG as a candidate for alternative treatment and prevention of coronavirus infection.

Keywords: coronavirus; diammonium glycyrrhizinate; broad spectrum; spike-mediated cellular entry; RBD-binding activity

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MDPI and ACS Style

Wu, S.; Yang, G.; Wang, K.; Yan, H.; Wang, H.; Li, X.; Qiao, L.; Wu, M.; Wang, Y.; Jiang, J.-D.; et al. Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry. Int. J. Mol. Sci. 2025, 26, 6334. https://doi.org/10.3390/ijms26136334

AMA Style

Wu S, Yang G, Wang K, Yan H, Wang H, Li X, Qiao L, Wu M, Wang Y, Jiang J-D, et al. Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry. International Journal of Molecular Sciences. 2025; 26(13):6334. https://doi.org/10.3390/ijms26136334

Chicago/Turabian Style

Wu, Shuo, Ge Yang, Kun Wang, Haiyan Yan, Huiqiang Wang, Xingqiong Li, Lijun Qiao, Mengyuan Wu, Ya Wang, Jian-Dong Jiang, and et al. 2025. "Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry" International Journal of Molecular Sciences 26, no. 13: 6334. https://doi.org/10.3390/ijms26136334

APA Style

Wu, S., Yang, G., Wang, K., Yan, H., Wang, H., Li, X., Qiao, L., Wu, M., Wang, Y., Jiang, J.-D., & Li, Y. (2025). Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry. International Journal of Molecular Sciences, 26(13), 6334. https://doi.org/10.3390/ijms26136334

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Diammonium Glycyrrhizinate Exerts Broad-Spectrum Antiviral Activity Against Human Coronaviruses by Interrupting Spike-Mediated Cellular Entry

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