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In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds

Mohd Abd Razak et al., Natural Product Communications, doi:10.1177/1934578X231188861

Sep 2023

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Curcumin for COVID-19

15th treatment shown to reduce risk in February 2021, now with p = 0.0000000096 from 27 studies.

Lower risk for mortality, ventilation, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 110 treatments. c19early.org

In vitro study showing that of 9 phenolic compounds tested, only curcumin inhibited SARS-CoV-2 cytopathic effects in infected monkey kidney Vero E6 cells. Curcumin showed antiviral activity against wildtype, alpha, delta, and omicron variants, with EC₅₀ values around 25µM for the variants and 13.63µM for the wildtype, but with a low selectivity index (SI < 5). Curcumin was more effective against SARS-CoV-2 infection in human lung A549 cells expressing ACE2 and TMPRSS2 receptors, with an EC₅₀ of 4.57μM and a higher selectivity index of 7.96. Curcumin also inhibited SARS-CoV-2 spike protein-ACE2 interaction and 3CL protease activity at 10-20μM concentrations. The results suggest curcumin has moderate antiviral activity against SARS-CoV-2 through multiple targets, although bioavailability may limit efficacy, requiring formulations for improved bioavailability.

Positive controls andrographolide, chloroquine, and remdesivir inhibited the viral-induced CPE with EC₅₀ values of less than 10μM with a high selectivity index (SI ≥ 10).

51 preclinical studies support the efficacy of curcumin for COVID-19:

26 In Silico studies1-26

24 In Vitro studies1,3,7,9,13,19,23,27-43

1 In Vivo animal study7

In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,2,7,12,14,20,23,44 (and specifically the receptor binding domainB,10,13,16), M^proC,2,7,9,11-13,15,16,18,21,23,24,26,40,44, RNA-dependent RNA polymeraseD,2,13,22,44, PLproE,2, ACE2F,14,15,17, nucleocapsidG,8,25, nsp10H,25, and helicaseI,29 proteins. In Vitro studies demonstrate inhibition of the spikeA,34 (and specifically the receptor binding domainB,43), M^proC,19,34,40,42, ACE2F,43, and TMPRSS2J,43 proteins, and inhibition of spike-ACE2 interactionK,27. In Vitro studies demonstrate efficacy in Calu-3L,41, A549M,34, 293TN,3, HEK293-hACE2O,19,32, 293T/hACE2/TMPRSS2P,33, Vero E6Q,9,13,23,32,34,36,37,39,41, and SH-SY5YR,31 cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants10, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells39, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress3, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts45, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity35.

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Study covers curcumin, HCQ, remdesivir, and andrographolide.

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15. Thapa et al., In-silico Approach for Predicting the Inhibitory Effect of Home Remedies on Severe Acute Respiratory Syndrome Coronavirus-2, Makara Journal of Science, doi:10.7454/mss.v27i3.1609.ac.id, doi.org.

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34. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

35. Fam et al., Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites, Scientific Reports, doi:10.1038/s41598-023-31764-9.nature.com, doi.org.

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44. Al balawi (B) 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.

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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 receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.

c. 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.

d. 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.

e. 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.

f. 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.

g. The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.

h. Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.

i. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.

j. 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.

k. The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.

l. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.

m. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.

n. 293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.

o. HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.

p. 293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.

q. Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.

r. SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.

Mohd Abd Razak et al., 16 Sep 2023, peer-reviewed, 11 authors. Contact: ridzuan.ar@moh.gov.my.

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

This Paper Curcumin All

In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds

Mohd Ridzuan Mohd Abd Razak, Nur Hana Md Jelas, Amirrudin Muhammad, Noorsofiana Padlan, Muhammad Nor Farhan Sa’at, Muhammad Afif Azizan, Siti Nur Zawani Rosli, E Kavithambigai Ellan, Murizal Zainol, Ravindran Thayan, Ami Fazlin Syed Mohamed

Natural Product Communications, doi:10.1177/1934578x231188861

Since the COVID-19 pandemic in 2020, many reports have highlighted several potential anti-SARS-CoV-2 drug candidates, including phenolic compounds. Therefore, this study aimed to evaluate the anti-SARS-CoV-2 activity of nine common phenolic compounds found in plants using the in vitro cellular infection model. The anti-SARS-CoV-2 activity of curcumin, quercetin, gallic acid, catechin, rutin, kaempferol, naringenin, coumaric acid and caffeic acid were evaluated on SARS-CoV-2-infected Vero E6 cells by using a cytopathic effect (CPE)-based assay. The anti-SARS-CoV-2 activity in human lung cells, A549 expressing human ACE2 and TMPRSS2, was evaluated by the RT-qPCR technique. S1-ACE2 interaction and 3CL protease activity assays were also performed for the potent compound. Of the nine phenolic compounds, only curcumin inhibited the SARS-CoV-2 induced CPE activity (EC 50 of 13.63 µM) in Vero E6 cells, but with a low selective index (SI) value. Interestingly, curcumin exhibited potent anti-SARS-CoV-2 activity in A549 cells with an EC 50 of 4.57 µM and an SI value of 7.96. S1-ACE2 interaction and 3CL protease inhibitory activities of curcumin were also observed. In conclusion, curcumin showed a moderate in vitro anti-SARS-CoV-2 activity. The true potential of curcumin as an anti-SARS-CoV-2 candidate could be further evaluated in a COVID-19 animal model.

Additional Information The data presented in this study are available on request from the corresponding author. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical Approval Ethical Approval is not applicable for this article. ORCID iD Mohd Ridzuan Mohd Abd Razak https://orcid.org/0000-0002-9589-5892 Statement of Human and Animal Rights This article does not contain any studies with human or animal subjects. Informed Consent There are no human subjects in this article and informed consent is not applicable.

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Therefore, this study aimed to ' 'evaluate the anti-SARS-CoV-2 activity of nine common phenolic compounds found in plants using ' 'the in vitro cellular infection model. The anti-SARS-CoV-2 activity of curcumin, quercetin, ' 'gallic acid, catechin, rutin, kaempferol, naringenin, coumaric acid and caffeic acid were ' 'evaluated on SARS-CoV-2-infected Vero E6 cells by using a cytopathic effect (CPE)-based ' 'assay. The anti-SARS-CoV-2 activity in human lung cells, A549 expressing human ACE2 and ' 'TMPRSS2, was evaluated by the RT-qPCR technique. S1-ACE2 interaction and 3CL protease ' 'activity assays were also performed for the potent compound. Of the nine phenolic compounds, ' 'only curcumin inhibited the SARS-CoV-2 induced CPE activity (EC50 of ' '13.63\u2005µM) in Vero E6 cells, but with a low selective index (SI) value. Interestingly, ' 'curcumin exhibited potent anti-SARS-CoV-2 activity in A549 cells with an ' 'EC50 of 4.57 µM and an SI value of 7.96. S1-ACE2 interaction and 3CL ' 'protease inhibitory activities of curcumin were also observed. In conclusion, curcumin showed ' 'a moderate in vitro anti-SARS-CoV-2 activity. The true potential of curcumin as an ' 'anti-SARS-CoV-2 candidate could be further evaluated in a COVID-19 animal model. 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Kavithambigai', 'family': 'Ellan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Infectious Disease Research Centre, Institute for Medical ' 'Research, National Institutes of Health, Ministry of Health ' 'Malaysia, Selangor, Malaysia'}]}, { 'given': 'Murizal', 'family': 'Zainol', 'sequence': 'additional', 'affiliation': [ { 'name': 'Herbal Medicine Research Centre, Institute for Medical Research, ' 'National Institutes of Health, Ministry of Health Malaysia, ' 'Selangor, Malaysia'}]}, { 'given': 'Ravindran', 'family': 'Thayan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Infectious Disease Research Centre, Institute for Medical ' 'Research, National Institutes of Health, Ministry of Health ' 'Malaysia, Selangor, Malaysia'}]}, { 'given': 'Ami Fazlin', 'family': 'Syed Mohamed', 'sequence': 'additional', 'affiliation': [ { 'name': 'Herbal Medicine Research Centre, Institute for Medical Research, ' 'National Institutes of Health, Ministry of Health Malaysia, ' 'Selangor, 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