Review of Natural Products with Promising Anti-SARS-CoV-2 Potential

In a recent review published in Research into phytotherapyresearchers examined existing literature on naturally active products with therapeutic efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Promising Natural Products Against SARS-CoV-2: Structure, Function and Clinical Trials. Image Credit: Olga Larionova/Shutterstock

Studies have reported breakthrough infections from coronavirus disease 2019 (COVID-19) and multiple mutations in SARS-CoV-2 variants, justifying the development of improved vaccines and drugs against COVID-19. Researchers have highlighted the anti-SARS-CoV-2 efficacy of natural products that could potentially expand the therapeutic landscape of SARS-CoV-2 infections.

About the review

In the current review, researchers rated natural products with promising anti-SARS-CoV-2 action based on relevant studies (molecular dockingin vitro cell experimentsin silicon screening) from databases such as SCI, PubMed, Chinese National Knowledge Infrastructure (CNKI), Clinical Trials Gov and the Chinese Registry of Clinical Trials (ChiCTR) between January 2020 and April 2022.

Pathophysiology of COVID-19

SARS-CoV-2 enters host cells via transmembrane serine protease 2 (TMPRSS2) or cathepsin (Cat)B/L, subsequently identified by ACE2 (angiotensin-converting enzyme 2) and other host cell receptors such as glucose-regulated protein 78 (GRP78) and cluster of differentiation 147 (CD147). SARS-CoV-2 then fuses to the host cell membrane and releases ribonucleic acid (RNA) into the host cell, with the help of furin protease.

SARS-CoV-2 RNA uses host precursor cells to synthesize -protease (Ppro) and 3C-like protease (3CLpro) that are cleaved into non-structural proteins (NSPs) and proteases necessary for RNA replication, such as RNA-dependent RNA polymerase (RdRp). On the host cell’s endoplasmic reticulum, viral RNA synthesizes structural proteins for viral assembly, such as SARS-CoV-2 spike (S) and nucleocapsid (N) protein, followed by the synthesis of SARS-CoV-2 progeny cells that invade more human tissues and organs. As a result, COVID-19 causes widespread inflammation (cytokine storm) and systemic disorders, including respiratory distress, hepatitis and kidney failure.

SARS-COV-2 infections lead to immunological dysregulation that significantly affects clinical recovery. SARS-CoV-2 3CLpro affects the type I interferon (IFN) level, while type I and III IFNs are involved in viremia control and regulation of the immune system. In addition, SARS-CoV-2 associated immune disorders can lead to autoimmune diseases and blood disorders such as hemolytic anemia.

Mechanism of anti-SARS-CoV-2 action of naturally active products

Natural products can be targeted to inhibit the invasion and replication of COVID-19, regulate immune balance or reduce inflammatory factors and suppress hyperimmunity. Polyphenols, flavonoids and alkaloids with multi-target pathways may be efficient against SARS-CoV-2. Baicalin, honokiol, curcumin, rutin, epigallocatechin gallate (ECGC), nicotinamine, kaempferol, chlorogenic acid, quercetin, and glycyrrhizin may block access to SARS-CoV-2.

Myricetin blocks the formation of NSP and berberine, indirubin, curcumin, β-sitosterol, betulinic acid and cordycepin inhibit the activity of Ppro and 3CLpro. Forsythosia, taraxacum sterol and parthenolide prevent systemic inflammation and organ dysfunction associated with COVID-19. Targeted inhibition of CD147 has been reported for pseudopolar acid B (PAB). EGCG targets GRP78 and regulates immune cell levels and immune factors. Astragalus polysaccharide (APS) regulates the CD4+/CD8+ ratio.

Of the natural products, EGCG, Caffeic Acid Phenethyl Ester (CPEA) and Resveratrol have multi-target and immunomodulatory effects, including stimulation of NK (natural killer) cell activity, increasing the number of T lymphocytes and B lymphocytes linked to neutralizing antibodies, increased (NAb) production and regulation of CD4+/CD8+ and helper T cells (Th)1/Th2 ratios.

Baicalin was found to be 3CLpro. to brake in vitro [half maximal inhibitory concentration (IC50 0.4 μM)]and in Vero cells [half maximal effective concentration (EC50 2.9 μM)] and several RCTs have reported improved COVID-19-associated lung damage and inflammation in COVID-19 patients. In addition to inhibiting ACE2 binding and 3CLpro activity, quercetin reduced the frequency and duration of hospitalization, the number of invasive oxygen therapies in COVID-19 patients and reduced extra-articular manifestations (EMS), pain and tumor necrosis factor alpha (TNF-α ) plasma levels in patients with rheumatoid arthritis (RA) and the extent of upper respiratory tract infections.

Rutin has reduced myeloperoxidase (MPO) levels in healthy women and improved the neurological and inflammatory status of patients [ox-low-density lipoprotein (LDL), nuclear factor kappa B (NF-κB) p65, TNF-α and interleukin 6 (IL-6)] in patients with acute cerebral infarction (ACI). In addition to 3CLpro inhibition, berberine has decreased IL levels in patients with acute coronary syndrome (ACS).

Betulinic acid has inhibited 3CLpro (IC50 of five M) and can activate the immune response by improving the CD4+/CD8+ ratio. Indirubin decreased the expression level of the pro-inflammatory factors IL-1β, IL-6 and TNF-α in mouse models. Cordycepin inhibited RdRp and 3CL pro with EC50 concentrations of 2 M in SARS-CoV-2 infected Vero E6 cells.

Glycyrrhizin has inhibited SARS-COV-2 infection with an EC50 of 2.4 m in Vero E6 cells and has been shown to regulate the expression of NF-KB, TNF-α, IL-6, HMGB1 (group box 1 high mobility protein), cyclooxygenase 2 (COX-2) in rats and improved liver function in hepatitis B patients. In SARS patients, glycyrrhizin reduced chest tightness, pain, cough, and improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in COVID-19 patients. Honokiol inhibited furin protein (99.8%) and SARS-COV-2 infections (99.9%) at 25 M and 50 M concentrations, respectively, in Vero E6/TMPRSS2 cells infected with SARS-COV-2 .

Conclusion

Based on the review’s findings, natural products such as flavonoids, polyphenols, polyterpenes, lactones and sterols may be considered COVID-19 vaccine enhancers or targeted anti-SARS-CoV-2 therapies. However, further research is needed with clinical potency assessments, safety verification testing, drug interaction testing, and clinical trials to substantiate the multi-target and multi-pathway anti-SARS-CoV-2 effects of such natural products.

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