Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level
Lina Wan, Yuchen Li, Wenhao Liao, Lizhen Lei, Maoyuan Zhao, Jinhao Zeng, Ziyi Zhao, Jianyuan Tang
Scientific Reports, doi:10.1038/s41598-024-54722-5
The SARS-CoV-2 virus, belonging to the Coronavirus genus, which poses a threat to human health worldwide. Current therapies focus on inhibiting viral replication or using anti-inflammatory/ immunomodulatory compounds to enhance host immunity. This makes the active ingredients of traditional Chinese medicine compounds ideal therapies due to their proven safety and minimal toxicity. Previous research suggests that andrographolide and baicalin inhibit coronaviruses; however, their synergistic effects remain unclear. Here, we studied the antiviral mechanisms of their synergistic use in vitro and in vivo. We selected the SARS-CoV-2 pseudovirus for viral studies and found that synergistic andrographolide and baicalein significantly reduced angiotensin-converting enzyme 2 protein level and viral entry of SARS-CoV-2 into cells compared to singal compound individually and inhibited the major protease activity of SARS-CoV-2. This mechanism is essential to reduce the pathogenesis of SARS-CoV-2. In addition, their synergistic use in vivo also inhibited the elevation of pro-inflammatory cytokines, including IL-6 and TNF-α-the primary cytokines in the development of acute respiratory distress syndrome (the main cause of COVID-19 deaths). In conclusion, this study shows that synergistic andrographolide and baicalein treatment acts as potent inhibitors of coronavirus mechanisms in vitro and in vivo-and is more effective together than in isolation. Since 2002, a zoonotic coronavirus that causes respiratory disease, including the severe acute respiratory syndromes coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus, and the recent 2019 SARS-CoV-2 has caused three outbreaks 1 . The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is the most significant global public health event with high pathogenicity and infectivity 2 . So far, hundreds of millions of test-positive cases and tens of thousands of deaths have been confirmed worldwide (https:// covid 19. who. int/) 3 . The Coronavirus genus includes SARS-CoV-2, which is an enveloped single-stranded positive-sense RNA virus with high pathogenicity. Its spike (S) protein mediates viral entry into host cells 2,4,5 , infecting human bronchial epithelial cells, upper respiratory tract cells, and lung cells, leading to irreversible lung damage, life-threatening respiratory diseases, and multi-organ failure 6 . Currently, there are no specific prevention or treatment methods available 4 . The genome RNA of SARS-CoV encodes a non-structural replicase polyprotein and structural proteins, including the S protein, nucleocapsid (N) protein, ion channel (E), and integral membrane (M) protein. The S protein is the most immunogenic of these proteins, and therefore related to vaccine development, diagnosis, and treatment 3,7 . The S protein consists of two subunits: the S1 subunit that binds to the host entry receptor angiotensin-converting enzyme 2 (ACE2) and the S2 subunit that mediates membrane fusion..
Author contributions L.W.: Methodology, performing the experiments, Formal analysis, Writing-original draft. Y.L.: Methodology, performing the experiments, Formal analysis. W.L.: Methodology, Formal analysis, Writing-review & editd. M.Z.: Methodology, performing the experiments, Formal analysis. L.L.: Methodology, performing the experiments, Formal analysis. J.Z.: Supervision. Z.Z.: Supervision. J.T.: Supervision, Writing-review & editing, Conceptualization, and coordinated the study. All authors have read and approved the final manuscript.
Competing interests The authors declare no competing interests.
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