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

• DOI: 10.1096/fj.202001792r
• Publication Date: 2021-03-22T14:31:36Z
• Authors: Zhen‐Zhen Wang; Kun Li; Anish R. Maskey; Weihua Huang; Anton A. Toutov; Nan Yang; Kamal Srivastava; Jan Geliebter; Raj Tiwari; Mingsan Miao; Xiu‐Min Li
• Keywords: 0301 basic medicine; Berberine; SARS-CoV-2; Administration, Oral; COVID-19; Severe Acute Respiratory Syndrome; Antiviral Agents; Models, Biological; Cell Line; COVID-19 Drug Treatment; 3. Good health; 03 medical and health sciences; Gene Expression Regulation; Severe acute respiratory syndrome-related coronavirus; Humans; Computer Simulation; Pandemics

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.