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.
References
Abdallah, El-Halawany, Sirwi, Repurposing of some natural product isolates as SARS-COV-2 main protease inhibitors via in vitro cell free and cell-based antiviral assessments and molecular modeling approaches, Pharmaceuticals
Abu-Raddad, Chemaitelly, Butt, National Study Group for C-V. Effectiveness of the BNT162b2 COVID-19 vaccine against the B.1.1.7 and B.1.351 variants, N Engl J Med
Accorsi, Britton, Ke, Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 omicron and Delta variants, JAMA
Agrawal, Agrawal, Blunden, Naringenin as a possible candidate against SARS-CoV-2 infection and in the pathogenesis of COVID-19, Nat Prod Commun,
doi:10.1177/1934578X211066723Agrawal, Agrawal, Blunden, Quercetin: antiviral significance and possible COVID-19 integrative considerations, Nat Prod Commun,
doi:10.1177/1934578X20976293Agrawal, Agrawal, Blunden, Rutin: a potential antiviral for repurposing as a SARS-CoV-2 main protease (mpro) inhibitor, Nat Prod Commun,
doi:10.1177/1934578X21991723Alzaabi, Hamdy, Ashmawy, Flavonoids are promising safe therapy against COVID-19, Phytochem Rev
Bahun, Jukic, Oblak, Inhibition of the SARS-CoV-2 3CL(pro) main protease by plant polyphenols, Food Chem
Bormann, Alt, Schipper, Turmeric root and its bioactive ingredient curcumin effectively neutralize SARS-CoV-2 in vitro, Viruses
Chemaitelly, Tang, Hasan, Waning of BNT162b2 vaccine protection against SARS-CoV-2 infection in Qatar, N Engl J Med
Chen, Shinn, Itkin, Drug repurposing screen for compounds inhibiting the cytopathic effect of SARS-CoV-2, Front Pharmacol,
doi:10.3389/fphar.2020.592737Choy, Wong, Kaewpreedee, Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro, Antiviral Res
Couzin-Frankel, Antiviral pills could change pandemic's course, Science
Drozdzal, Rosik, Lechowicz, An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment, Drug Resist Updat
El Gizawy, Boshra, Mostafa, bioactive constituents exert anti-SARS-CoV-2 and antiinflammatory activities: molecular docking and dynamics, in vitro, and in vivo studies, Molecules
Elfiky, Natural products may interfere with SARS-CoV-2 attachment to the host cell, J Biomol Struct Dyn
Fischer Wa 2nd, Eron, Jr, Holman, A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus, Sci Transl Med
Goc, Sumera, Rath, Niedzwiecki, Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions, PLoS One
Gordon, Jang, Bouhaddou, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature
Harvey, Carabelli, Jackson, SARS-CoV-2 variants, spike mutations and immune escape, Nat Rev Microbiol
Hoffmann, Mosbauer, Hofmann-Winkler, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature
Jena, Kanungo, Nayak, Chainy, Dandapat, Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies, Sci Rep
Kanjanasirirat, Suksatu, Manopwisedjaroen, High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS-CoV-2 agents, Sci Rep
Mangiavacchi, Botwina, Menichetti, Selenofunctionalization of quercetin improves the non-covalent inhibition of M(pro) and its antiviral activity in cells against SARS-CoV-2, Int J Mol Sci
Marin-Palma, Tabares-Guevara, Zapata-Cardona, Curcumin inhibits in vitro SARS-CoV-2 infection in Vero E6 cells through multiple antiviral mechanisms, Molecules
Mosmann, Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, J Immunol Methods
Nguyen, Jung, Kim, The inhibitory effects of plant derivate polyphenols on the main protease of SARS coronavirus 2 and their structure-activity relationship, Molecules
Polack, Thomas, Kitchin, Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine, N Engl J Med
Rebello, Beyl, Lertora, Safety and pharmacokinetics of naringenin: a randomized, controlled, single-ascending-dose clinical trial, Diabetes Obes Metab
Sa-Ngiamsuntorn, Suksatu, Pewkliang, Anti-SARS-CoV-2 activity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives, J Nat Prod
Sancineto, Ostacolo, Ortega-Alarcon, L-Arginine improves solubility and Anti-SARS-CoV-2 Mpro activity of rutin but not the antiviral activity in cells, Molecules
Stohs, Ji, Bucci, Preuss, A comparative pharmacokinetic assessment of a novel highly bioavailable curcumin formulation with 95% curcumin: a randomized, double-blind, crossover study, J Am Coll Nutr
Teli, Shah, Chhabria, In silico screening of natural compounds as potential inhibitors of SARS-CoV-2 main protease and spike RBD: targets for COVID-19, Front Mol Biosci,
doi:10.3389/fmolb.2020.599079Vahedian-Azimi, Abbasifard, Rahimi-Bashar, Effectiveness of curcumin on outcomes of hospitalized COVID-19 patients: a systematic review of clinical trials, Nutrients
Vangeel, Chiu, Jonghe, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern, Antiviral Res
Voysey, Clemens, Madhi, Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK, Lancet
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Zhang, Zeng, Pan, Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial, Lancet Infect Dis
Zhang, Zhang, Li, A cell-based large-scale screening of natural compounds for inhibitors of SARS-CoV-2, Signal Transduct Target Ther
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