Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (M pro ), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3′,5′-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.

Paving new roads toward the advancement of broad‐spectrum antiviral agents

“…It is widely accepted that antiviral TCMs can act by both preventing viral systemic spread through immuno-stimulation, and by enhancing the host's tolerance to virus infection through the suppression of overactivated inflammatory responses. 67,68 In addition, the diverse chemical structures within TCM constitutions may have the capacity to recognize at least one of the pivotal viral components, regardless of the virus species, thus directly blocking virus replication as a complementary mechanism of action. 68 These features enhance the efficacy of these antiviral TCMs in treating multiple virus infections, with only slight modifications of the recipe required to accommodate the differentiated clinical syndromes.…”

“…67,68 In addition, the diverse chemical structures within TCM constitutions may have the capacity to recognize at least one of the pivotal viral components, regardless of the virus species, thus directly blocking virus replication as a complementary mechanism of action. 68 These features enhance the efficacy of these antiviral TCMs in treating multiple virus infections, with only slight modifications of the recipe required to accommodate the differentiated clinical syndromes.…”

Theory and scientificity of traditional Chinese medicine

“…In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3′,5′-cyclic phosphodiesterase 4 (PDE4), and both compounds bind in the active site of PDE4 with similar interactions. [31] These results suggested that the synergistic effect of multicomponents and multitargets might be the reason for TCMFs to exert clinical efficacy.…”

“…[75–77] These effects are probably through the mechanism of inhibiting the SARS-COV-2 replication and reducing proinflammatory cytokines. [31,78,79] The 12-month results of the largest longitudinal cohort study of COVID-19 hospitalized adult survivors to date showed that many COVID-19 patients will fully recover after more than 1 year. [80]…”

“Three medicines and three formulas” in COVID-19: From bench to bedside

“…Among these, echinatin and quercetin were identified as inhibitors of main protease (3CL pro ), while glycyrrhisoflavone and licoisoflavone A were found to inhibit the RNA-dependent RNA polymerase (RdRp). Additionally, three anti-inflammatory components, namely licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model [100] . From network pharmacological analysis, eight common targets, including FYN, SFTPD, P53, retinol-binding protein 4 (RBP4), IL1RN, TTR, serine/arginine protein kinase1 (SRPK1), and AKT1, were identified by overlapping the targets of HSBD and COVID-19.…”