*Article* **Glycyrrhizic Acid Inhibits SARS-CoV-2 Infection by Blocking Spike Protein-Mediated Cell Attachment**

**Jingjing Li 1,2,3,†, Dongge Xu 1,2,4,†, Lingling Wang 1,2,5, Mengyu Zhang 1,2,4, Guohai Zhang 6, Erguang Li 1,2,7,\* and Susu He 1,2,4,\***


**Abstract:** Glycyrrhizic acid (GA), also known as glycyrrhizin, is a triterpene glycoside isolated from plants of *Glycyrrhiza* species (licorice). GA possesses a wide range of pharmacological and antiviral activities against enveloped viruses including severe acute respiratory syndrome (SARS) virus. Since the S protein (S) mediates SARS coronavirus 2 (SARS-CoV-2) cell attachment and cell entry, we assayed the GA effect on SARS-CoV-2 infection using an S protein-pseudotyped lentivirus (Lenti-S). GA treatment dose-dependently blocked Lenti-S infection. We showed that incubation of Lenti-S virus, but not the host cells with GA prior to the infection, reduced Lenti-S infection, indicating that GA targeted the virus for infection. Surface plasmon resonance measurement showed that GA interacted with a recombinant S protein and blocked S protein binding to host cells. Autodocking analysis revealed that the S protein has several GA-binding pockets including one at the interaction interface to the receptor angiotensin-converting enzyme 2 (ACE2) and another at the inner side of the receptor-binding domain (RBD) which might impact the close-to-open conformation change of the S protein required for ACE2 interaction. In addition to identifying GA antiviral activity against SARS-CoV-2, the study linked GA antiviral activity to its effect on virus cell binding.

**Keywords:** glycyrrhizin; SARS-CoV-2; surface plasmon resonance; autodocking
