Computational and experimental evidence of the anti‐COVID‐19 potential of honeybee propolis ingredients, caffeic acid phenethyl ester and artepillin c

Kumar et al., Phytotherapy Research, doi:10.1002/ptr.7717, Feb 2023

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In Silico and In Vitro study showing anti-COVID-19 potential of honeybee propolis ingredients caffeic acid phenethyl ester and artepillin C through inhibition of ACE2 and TMPRSS2.

12 preclinical studies support the efficacy of propolis for COVID-19:

6 In Silico studies1-6

6 In Vitro studies2,4,6-9

In Silico studies predict inhibition of SARS-CoV-2 with propolis or metabolites via binding to the spikeA,1,2, M^proB,2, RNA-dependent RNA polymeraseC,1,2, PLproD,1, ACE2E,6, and TMPRSS2F,6 proteins. In Vitro studies demonstrate inhibition of the ACE2E,6 and TMPRSS2F,6 proteins. Propolis may inhibit spike protein and ACE2 interaction8, may inhibit SARS-CoV-2 through interactions with MAPK15, inhibited SARS-CoV-2 in Vero E6 cells at a concentration comparable to a combination of four antiviral components9, may mitigate hyperinflammation via STAT1, NOS2, and BTK targeting3, may inhibit SARS-CoV-2 entry by interfering with ACE2/TMPRSS2 interaction7, components of propolis show ACE2 downregulation in human cells6, modulates inflammatory responses by reducing pro-inflammatory cytokines IL-1β, IL-6, and TNF-α7, and may suppress Epstein-Barr Virus reactivation3.

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1. Ferreira Júnior et al., An In Silico Investigation of Brazilian Green Propolis Extracts as Potential Treatment for COVID-19, ACS Omega, doi:10.1021/acsomega.5c02121.acs.org, doi.org.

2. Al balawi et al., Assessing multi-target antiviral and antioxidant activities of natural compounds against SARS-CoV-2: an integrated in vitro and in silico study, Bioresources and Bioprocessing, doi:10.1186/s40643-024-00822-z.springeropen.com, doi.org.

3. Anshori et al., Uncovering the Therapeutic Potential of Propolis Extract in Managing Hyperinflammation and Long COVID‐19: A Comprehensive Bioinformatics Study, Chemistry & Biodiversity, doi:10.1002/cbdv.202401947.wiley.com, doi.org.

4. Ay et al., Investigation of The Inhibition of SARS-CoV-2 Spike RBD and ACE-2 Interaction by Phenolics of Propolis Extracts, Journal of Apitherapy and Nature, doi:10.35206/jan.1471090.org.tr, doi.org.

5. Siregar et al., Exploring Therapeutic Potential of Nutraceutical Compounds from Propolis on MAPK1 Protein Using Bioinformatics Approaches as Anti-Coronavirus Disease 2019 (COVID-19), BIO Web of Conferences, doi:10.1051/bioconf/20248800007.bio-conferences.org, doi.org.

6. Kumar et al., Computational and experimental evidence of the anti‐COVID‐19 potential of honeybee propolis ingredients, caffeic acid phenethyl ester and artepillin c, Phytotherapy Research, doi:10.1002/ptr.7717.wiley.com, doi.org.

7. Ferreira et al., Antiviral and anti-inflammatory efficacy of nanoencapsulated brazilian green propolis against SARS-CoV-2, Scientific Reports, doi:10.1038/s41598-025-05683-w.nature.com, doi.org.

8. dos Santos et al., Countercurrent chromatography isolation of green propolis biomarkers: potential blockers of SARS-CoV-2 RBD and ACE2 interaction, Journal of Chromatography A, doi:10.1016/j.chroma.2024.465265.sciencedirect.com, doi.org.

9. Karaoğlu et al., Chewable tablet with herbal extracts and propolis arrests Wuhan and Omicron variants of SARS-CoV-2 virus, Journal of Functional Foods, doi:10.1016/j.jff.2023.105544.sciencedirect.com, doi.org.

a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.

b. The main protease or M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.

c. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.

d. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.

e. The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.

f. Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.

Kumar et al., 9 Feb 2023, peer-reviewed, 11 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Propolis All

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