Abstract
Currently, human health due to corona virus disease 2019 (COVID-19) pandemic has been seriously threatened. The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19. However, the efficacy is compromised by the SARS-CoV-2 evolvement and mutation. Here we report the SARS-CoV-2 S protein receptor-binding domain (RBD) inhibitor licorice-saponin A3 (A3) could widely inhibit RBD of SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, XBB and BQ1.1. Furthermore, A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells, with EC50 of 1.016 μM. The mechanism was related with binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis combined with quantum mechanics/molecular mechanics (QM/MM) simulations. Interestingly, phosphoproteomics analysis and multi fluorescent immunohistochemistry (mIHC) respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 MAPK pathways and rebalancing the corresponding immune dysregulation. This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.