Potential of diterpenoid andrographolide in COVID-19 therapy: an insight on its antiviral-, immunomodulatory-, anti-inflammatory-, antioxidant- and antithrombotic- properties

• Andrographolide (Andro) in vitro inhibits SARS-CoV-2 replication at low micromolar concentrations in different cell lines. • Andro inhibits activity of SARS-CoV-2 and SARS-CoV main proteases through covalent linkages. • Andro through covalent modification of Cys62 in p50 inhibits the transcriptional activity of NF-κB in inflammation. • Andro targets p38 MAPK/Nrf2/HO-1 axis in suppression of viral infection and inflammation. • Andro prevents PAF-induced platelet aggregation in human blood. • Andro is effective in treatment of COVID-19 infection in the early stages. Highly effective clinical drugs need to be developed to treat the infection of SARS-CoV-2 in COVID-19 pandemic. Andrographolide (Andro), a bioactive labdane diterpenoid isolated from Andrographis paniculata Nees, has various pharmacological activities including antiviral and anti-inflammatory activities. The study aimed to search extensively the efficacy of Andro against COVID-19 infection and its associated complications and any adverse events. We collected the relevant information presented in this review from scientific literature databases, including Google Scholar, Science-Direct, PubMed and Scifinder using keywords, coronavirus, COVID-19, andrographolide, Andrographis paniculata , pharmacological activity, toxicity and safety. More than 400 units of literature were screened and those relevant to this review were considered. The results showed that Andro effectively inhibits the replication of multiple strains of SARS-CoV-2 in different cell lines including human lung epithelial Calu-3 cells superior to remdesivir (IC 50 , 0.034 vs. 0.086 µM) and targets the activity of host ACE2 and viral 3CL-proteases. Moreover, Andro prevents sepsis-related complications in influenza virus-infected or LPS-treated mice, by suppression of inflammation, accumulation of macrophages and neutrophils and oxidative stress in lung tissues through deactivation of NF-κB (via covalent modification of Cys62 of p50) and JAK/STAT and activation of Nrf2/HO-1 pathways. Andro also effectively inhibits PAF-induced platelet aggregation in human blood without inducing toxicity in PBMC up to 50 µM. In clinical trials in mild COVID-19 patients, Andro and its sulphonates in “Xiyanping” injection (XYP) are safe and effective in suppression of pneumonia. The current findings suggest that Andro/XYP could be a promising therapeutic option for COVID-19.