Study: Promising natural products against SARS-CoV-2: Structure, function, and clinical trials. Image Credit: Olga Larionova/Shutterstock

A review of natural products with promising potential against SARS-CoV-2

In a recent review published in Phytotherapy researchresearchers reviewed the 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 studies. Image credit: Olga Larionova/Shutterstock

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

About the review

In this review, researchers evaluated natural products with promising activity against SARS-CoV-2 based on relevant studies (molecular dockingin vitro cell experimentsin silico screening) from databases such as SCI, PubMed, China National Knowledge Infrastructure (CNKI), Clinical Trials Gov and China Clinical Trials Registry (ChiCTR) between January 2020 and April 2022.

Pathophysiology of COVID-19

SARS-CoV-2 enters host cells by transmembrane serine protease 2 (TMPRSS2) or cathepsin (Cat)B/L, then is 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). Subsequently, SARS-CoV-2 fuses with 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 cells to synthesize P-protease (Ppro) and 3C-like protease (3CLpro), which are cleaved into nonstructural proteins (NSPs) and proteases required for RNA replication, such as RNA-dependent RNA polymerase ( RdRp). At the endoplasmic reticulum of the host cell, viral RNA synthesizes structural proteins for virus assembly, such as the SARS-CoV-2 spike (S) and nucleocapsid (N) protein, followed by the synthesis of SARS-CoV-2 progeny cells invading multiple 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 type I interferon (IFN) levels, while type I and III IFNs are involved in viremia control and immune system regulation. In addition, immune disorders associated with SARS-CoV-2 can lead to autoimmune diseases and blood disorders such as hemolytic anemia.

Anti-SARS-CoV-2 mechanism of action of naturally active products

Natural products can be aimed at inhibiting the invasion and replication of COVID-19, regulating the immune balance or reducing inflammatory factors and suppressing hyperimmunity. Polyphenols, flavonoids, and alkaloids with multitarget pathways may be effective against SARS-CoV-2. Baicalin, honokiol, curcumin, rutin, epigallocatechin gallate (ECGC), nicotinamine, kaempferol, chlorogenic acid, quercetin, and glycyrrhizin can block the entry of SARS-CoV-2.

Myricetin blocks NSP formation, and berberine, indirubin, curcumin, β-sitosterol, betulinic acid, and cordycepin inhibit Ppro and 3CLpro activity. 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 action and immunomodulatory effects, including stimulation of NK (natural killer) cell activity, increase in the number of T lymphocytes and B lymphocytes associated with neutralizing antibody (NAb) production and regulation of CD4+/ CD8+ and helper T cells (Th)1/Th2.

Baicalin was found to inhibit 3CLpro 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 improvements in lung injury and inflammation associated with COVID-19 in patients with COVID-19. In addition to inhibiting ACE2 binding and 3CLpro activity, quercetin reduced the frequency and duration of hospitalization, the rate of invasive oxygen therapy in patients with COVID-19, and reduced extra-articular manifestations (EMS), pain, and tumor necrosis factor alpha (TNF-). (a) plasma levels in patients with rheumatoid arthritis (RA) and grade of upper respiratory tract infections.

Rutin 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 inhibiting 3CLpro, berberine reduced IL levels in patients with acute coronary syndrome (ACS).

Betulinic acid inhibited 3CLpro (IC50 5 μM) and may activate the immune response by improving the CD4+/CD8+ ratio. Indirubin reduced the expression level of pro-inflammatory factors IL-1β, IL-6 and TNF-α in mouse models. Cordycepin inhibited RdRp and 3CL pro with EC50 concentrations of 2 μM in SARS-CoV-2-infected Vero E6 cells.

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

Conclusion

Based on the review results, natural products such as flavonoids, polyphenols, polyterpenes, lactones, and sterols can be considered as COVID-19 vaccine boosters or targeted therapeutics against SARS-CoV-2. However, further research with clinical efficacy evaluation, safety validation tests, drug interaction tests, and clinical trials is needed to confirm the multi-target and multi-pathway anti-SARS-CoV-2 effects of such natural products.

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