A small molecule compound berberine as an orally active therapeutic candidate against COVID‐19 and SARS: A computational and mechanistic study

The novel coronavirus disease, COVID‐19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID‐19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID‐19 and SARS, including antiviral, anti‐allergy and inflammation, hepatoprotection against drug‐ and infection‐induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti‐influenza, anti‐hepatitis C, anti‐cytomegalovirus, and anti‐alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID‐19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS‐CoV and SARS‐CoV‐2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID‐19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein‐protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic‐berberine nanomedicine, named NIT‐X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN‐γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS‐CoV‐2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL‐1α, IL‐8, IL‐6, and CCL‐2 in SARS‐CoV‐2 infected Calu3 cells were significantly suppressed by NIT‐X. By supporting protective immunity while inhibiting pro‐inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID‐19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID‐19 and SARS.