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

Abstract

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 infectioninduced 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, anticytomegalovirus, 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 2 of 19 | WANG et Al. 1 | INTRODUCTION Coronavirus disease-19 (COVID-19) is an infectious disease caused by a newly discovered coronavirus SARS-CoV2 that has reached global pandemic status and become a major global health threat. As of December 1 2020, there have been 63,751,931 confirmed cases and 1,477,976 deaths worldwide. 1 The United States hit record-high daily COVID-19 cases in November, 2020. Since the pandemic started in March, 2020, the nation has surpassed 12 million cases and more than 266,000 Americans have died. United States could see "a surge upon a surge" of COVID-19 cases this winter. 2 During just two full days at the end of November, 2020, the country saw over 360,000 new COVID-19 cases nationwide, in addition to over 2,700 new deaths. In 2003, a zoonotic coronavirus outbreak of SARS-CoV had resulted in severe SARS with fatality rates of 10%. 3-6 The SARS-CoV-2 genome shares approximately 70%-80% sequence similarity to SARS-CoV, and causes similar clinical symptoms. 7,8 Key clinical features of COVID-19 and SARS include fever, chills, muscle pain, headache, sore throat, new loss of taste or smell, cough, shortness of breath, gastrointestinal problems in mild to moderate cases, and more serious disease involving pneumonia, acute respiratory distress syndrome, cardiovascular and hepatic failure with high morbidity. 7,8 Individuals with pre-existing conditions like cardiovascular disease, hypertension, asthma, and diabetes, 9 and elderly patients are at a higher risk to become infected with severe symptoms. 10 To date, no specific therapeutic drug or vaccine COVID-19 and SARS is available, resulting in an urgent need for broad-spectrum therapeutics for COVID-19 and other CoV infections.

Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro

“…Our data also show that berberine chloride (BBC) can reduce SARS-CoV-2 replication, similar to what has been found by others [55,56]. BBC was able to block SARS-CoV-2 infectious virus production when added 6 h after the infection was started.…”

Changes in Sewage Sludge Chemical Signatures During a COVID‐19 Community Lockdown, Part 2: Nontargeted Analysis of Sludge and Evaluation with COVID‐19 Metrics

“…Berberine is a substance that shows a broad range of biochemical and pharmacological activities (i.e., anticancer, anti‐inflammatory, antiviral, and antidepressant) and has been proposed for COVID treatment in multiple studies (Varghese et al, 2021 ; Z. Z. Wang et al, 2021 ; Warowicka et al, 2020 ). We did not find any significant correlation for hydroxychloroquine, a highly publicized potential treatment for COVID‐19.…”

“…Wastewater and sludge samples used in these (and other) surveillance studies have also been leveraged for evaluating the scale and the direct and indirect impacts of outbreaks and associated lockdowns by examining changes in drug consumption, chemical usage, and chemical biomarkers (Choi et al, 2018 ; Lu et al, 2020 ; Reinstadler et al, 2021 ; Senta et al, 2020 ; Varghese et al, 2021 ; Z. Z. Wang et al, 2021 ). In Part 1 of this series, we used both targeted and suspect screening approaches with liquid chromatography—high resolution mass spectrometry (LC‐HRMS) to identify chemicals of interest in primary sewage sludge samples collected over the first 15 weeks of the COVID‐19 pandemic in New Haven, Connecticut, USA, and investigated trends over time during the initial lockdown and reopening phases (Nason et al, 2021 ).…”

Targeting autophagy with natural products to prevent SARS-CoV-2 infection

“…Molecular docking and dynamics simulations revealed that BBR significantly interacts with SARS-CoV-2 3CL PRO , S protein, and ACE2 receptor 59 , 60 , 61 ( Table 1 ). This suggests that BBR could prevent viral entry and fusion and interfere with the autophagy processes and the biogenesis of DMV by affecting the 3CL PRO -mediated generation of nsps 4–16.…”

“…Nonetheless, low bioavailability could be overcome through the inclusion of the natural biomolecules in lipid-based nanoparticles. 61 , 74 Since viruses need to import or synthesize lipid constituents to make DMVs, 62 we theorize that herbal-loaded lipid-nanocarriers, especially those that target nsps involved in the DMV biogenesis and inhibition of the autophagy flux, could be a smart way to easier penetrate cells, modulate autophagy, and hinder SARS-CoV-2. However, since CoVs can create a variety of strategies to use or mimic the host autophagic machinery to replicate, uncovering unexplored autophagy signaling pathways and mechanisms involved in the SARS-CoV-2 infection may open other possibilities for the use of phytocompounds.…”