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Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors

Emam et al., AMB Express, doi:10.1186/s13568-024-01739-8

Sep 2024

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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 109 treatments. c19early.org

In Vitro study showing that curcumin, quercetin, gallic acid, and silymarin inhibit SARS-CoV-2 spike protein binding to the ACE2 receptor. Authors developed a novel immunofluorescent assay to screen potential inhibitors of the spike-ACE2 interaction. Curcumin demonstrated the strongest inhibitory effect with an IC₅₀ of 1.4 μg/mL, followed by gallic acid (4.9 μg/mL), quercetin (8.5 μg/mL), and silymarin (21.0 μg/mL), compared to 12.7 μg/mL for the positive control chitosan nanoparticles. Cytotoxicity was evaluated in Vero cells, with CC₅₀ values of 13 μg/mL for curcumin, 18 μg/mL for gallic acid, 73 μg/mL for quercetin, and 65 μg/mL for silymarin.

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

24 In Silico studies1-24

23 In Vitro studies1,5,7,11,17,21,25-41

1 In Vivo animal study5

In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,5,10,12,18,21 (and specifically the receptor binding domainB,8,11,14), M^proC,5,7,9-11,13,14,16,19,21,22,24,38, RNA-dependent RNA polymeraseD,11,20, ACE2E,12,13,15, nucleocapsidF,6,23, nsp10G,23, and helicaseH,27 proteins. In Vitro studies demonstrate inhibition of the spikeA,32 (and specifically the receptor binding domainB,41), M^proC,17,32,38,40, ACE2E,41, and TMPRSS2I,41 proteins, and inhibition of spike-ACE2 interactionJ,25. In Vitro studies demonstrate efficacy in Calu-3K,39, A549L,32, 293TM,1, HEK293-hACE2N,17,30, 293T/hACE2/TMPRSS2O,31, Vero E6P,7,11,21,30,32,34,35,37,39, and SH-SY5YQ,29 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 variants8, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells37, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress1, 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 fibroblasts42, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity33.

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Study covers quercetin and curcumin.

1. Zhang et al., Computational Discovery of Mitochondrial Dysfunction Biomarkers in Severe SARS-CoV-2 Infection: Facilitating Pytomedicine Screening, Phytomedicine, doi:10.1016/j.phymed.2024.155784.sciencedirect.com, doi.org.

2. Öztürkkan et al., In Silico investigation of the effects of curcuminoids on the spike protein of the omicron variant of SARS-CoV-2, Baku State University Journal of Chemistry and Material Sciences, 1:2, bsuj.bsu.edu.az/uploads/pdf/ec4204d62f7802de54e6092bf7860029.pdf.edu.az.

3. Yunze et al., Therapeutic effect and potential mechanism of curcumin, an active ingredient in Tongnao Decoction, on COVID-19 combined with stroke: a network pharmacology study and GEO database mining, Research Square, doi:10.21203/rs.3.rs-4329762/v1.researchsquare.com, doi.org.

4. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.com, doi.org.

5. Boseila et al., Throat spray formulated with virucidal Pharmaceutical excipients as an effective early prophylactic or treatment strategy against pharyngitis post-exposure to SARS CoV-2, European Journal of Pharmaceutics and Biopharmaceutics, doi:10.1016/j.ejpb.2024.114279.sciencedirect.com, doi.org.

6. Hidayah et al., Bioinformatics study of curcumin, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin compounds in Curcuma longa as an antiviral agent via nucleocapsid on SARS-CoV-2 inhibition, International Conference on Organic and Applied Chemistry, doi:10.1063/5.0197724.aip.org, doi.org.

7. Singh et al., Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach, Research Square, doi:10.21203/rs.3.rs-3888947/v1.researchsquare.com, doi.org.

8. Kant et al., Structure-based drug discovery to identify SARS-CoV2 spike protein–ACE2 interaction inhibitors, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2023.2300060.tandfonline.com, doi.org.

9. Naderi Beni et al., In silico studies of anti-oxidative and hot temperament-based phytochemicals as natural inhibitors of SARS-CoV-2 Mpro, PLOS ONE, doi:10.1371/journal.pone.0295014.plos.org, doi.org.

10. Moschovou et al., Exploring the Binding Effects of Natural Products and Antihypertensive Drugs on SARS-CoV-2: An In Silico Investigation of Main Protease and Spike Protein, International Journal of Molecular Sciences, doi:10.3390/ijms242115894.mdpi.com, doi.org.

11. Eleraky et al., Curcumin Transferosome-Loaded Thermosensitive Intranasal in situ Gel as Prospective Antiviral Therapy for SARS-Cov-2, International Journal of Nanomedicine, doi:10.2147/IJN.S423251.dovepress.com, doi.org.

12. Singh (B) et al., Computational studies to analyze effect of curcumin inhibition on coronavirus D614G mutated spike protein, The Seybold Report, doi:10.17605/OSF.IO/TKEXJ.ac.in, doi.org.

13. 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.

14. Srivastava et al., Paradigm of Well-Orchestrated Pharmacokinetic Properties of Curcuminoids Relative to Conventional Drugs for the Inactivation of SARS-CoV-2 Receptors: An In Silico Approach, Stresses, doi:10.3390/stresses3030043.mdpi.com, doi.org.

15. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

16. Winih Kinasih et al., Analisis in silico interaksi senyawa kurkuminoid terhadap enzim main protease 6LU7 dari SARS-CoV-2, Duta Pharma Journal, doi:10.47701/djp.v3i1.2904.ac.id, doi.org.

17. Wu et al., Potential Mechanism of Curcumin and Resveratrol against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-2780614/v1.researchsquare.com, doi.org.

18. Nag et al., Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105552.sciencedirect.com, doi.org.

19. Rampogu et al., Molecular Docking and Molecular Dynamics Simulations Discover Curcumin Analogue as a Plausible Dual Inhibitor for SARS-CoV-2, International Journal of Molecular Sciences, doi:10.3390/ijms23031771.mdpi.com, doi.org.

20. Singh (C) et al., Potential of turmeric-derived compounds against RNA-dependent RNA polymerase of SARS-CoV-2: An in-silico approach, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2021.104965.sciencedirect.com, doi.org.

21. Kandeil et al., Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2, Pathogens, doi:10.3390/pathogens10060758.mdpi.com, doi.org.

22. Rajagopal et al., Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach, Future Journal of Pharmaceutical Sciences, doi:10.1186/s43094-020-00126-x.springeropen.com, doi.org.

23. Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.preprints.org, doi.org.

24. Sekiou et al., In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2, ChemRxiv, doi:10.26434/chemrxiv.12181404.v1.chemrxiv.org, doi.org.

25. Emam et al., Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors, AMB Express, doi:10.1186/s13568-024-01739-8.springeropen.com, doi.org.

26. Van Tin et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.mdpi.com, doi.org.

27. Li et al., Thermal shift assay (TSA)-based drug screening strategy for rapid discovery of inhibitors against the Nsp13 helicase of SARS-CoV-2, Animals and Zoonoses, doi:10.1016/j.azn.2024.06.001.sciencedirect.com, doi.org.

28. Kamble et al., Nanoparticulate curcumin spray imparts prophylactic and therapeutic properties against SARS-CoV-2, Emergent Materials, doi:10.1007/s42247-024-00754-6.springer.com, doi.org.

29. Nicoliche et al., Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2, Scientific Reports, doi:10.1038/s41598-024-61662-7.nature.com, doi.org.

30. Nittayananta et al., A novel film spray containing curcumin inhibits SARS-CoV-2 and influenza virus infection and enhances mucosal immunity, Virology Journal, doi:10.1186/s12985-023-02282-x.biomedcentral.com, doi.org.

31. Septisetyani et al., Curcumin and turmeric extract inhibited SARS-CoV-2 pseudovirus cell entry and Spike mediated cell fusion, bioRxiv, doi:10.1101/2023.09.28.560070.biorxiv.org, doi.org.

32. 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.

33. 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.

34. Teshima et al., Antiviral activity of curcumin and its analogs selected by an artificial intelligence-supported activity prediction system in SARS-CoV-2-infected VeroE6 cells, Natural Product Research, doi:10.1080/14786419.2023.2194647.tandfonline.com, doi.org.

35. Leka et al., In vitro antiviral activity against SARS-CoV-2 of common herbal medicinal extracts and their bioactive compounds, Phytotherapy Research, doi:10.1002/ptr.7463.wiley.com, doi.org.

36. Goc et al., Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants, European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022.akjournals.com, doi.org.

37. Marín-Palma et al., Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms, Molecules, doi:10.3390/molecules26226900.mdpi.com, doi.org.

38. Bahun et al., Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols, Food Chemistry, doi:10.1016/j.foodchem.2021.131594.sciencedirect.com, doi.org.

39. Bormann et al., Turmeric Root and Its Bioactive Ingredient Curcumin Effectively Neutralize SARS-CoV-2 In Vitro, Viruses, doi:10.3390/v13101914.mdpi.com, doi.org.

40. Guijarro-Real et al., Potential In Vitro Inhibition of Selected Plant Extracts against SARS-CoV-2 Chymotripsin-Like Protease (3CLPro) Activity, Foods, doi:10.3390/foods10071503.mdpi.com, doi.org.

41. Goc (B) et al., Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions, PLOS ONE, doi:10.1371/journal.pone.0253489.plos.org, doi.org.

42. Van Tin (B) et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.mdpi.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 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 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. 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.

g. 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.

h. 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.

i. 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.

j. 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.

k. 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.

l. 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.

m. 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.

n. 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.

o. 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.

p. 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.

q. 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.

Emam et al., 16 Sep 2024, peer-reviewed, 4 authors.

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

This Paper Curcumin All

Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors

Samah A Loutfy, Merna H Emam, Mohamed I Mahmoud, Nadia El-Guendy

doi:10.1186/s13568-024-01739-8

drug to be approved in 2020 for the treatment of hospitalized or non-hospitalized patients at high risk for COVID-19 disease progression (Lamb 2020). Following Remdesivir, Tocilizumab (Actemra®) and Baricitinib (Olumiant®), immunosuppressive drugs used for the treatment of rheumatoid arthritis, were approved in 2022 for the treatment of COVID-19 in hospitalized adults who are receiving systemic corticosteroids and require supplemental oxygen, ventilation, or extracorporeal membrane oxygenation (ECMO) (Assadiasl et al. 2021; Bozorgmanesh et al. 2021) . Spike protein is a surface protein of the SARS-CoV-2 virus that mediates viral adhesion and fusion by interaction with the angiotensin-converting enzyme 2 (ACE2) receptor expressed on the surface of the host cells (Scialo et al. 2020) . Spike-ACE2 protein-protein interaction (PPI) is a significant step in virus replication and has been

Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s13568-024-01739-8. Supplementary Material 1 Author contributions M.H.E performed the cytotoxicity in-vitro assays, as well as the immunofluorescent screening assay, conducted the graphical analysis for the results, and initiated the writing of the original draft. M.I.M produced and purified the in-house spike protein, conducted the graphical analysis for the results, and participated in the writing of the manuscript. All experiments were conducted under the supervision and guidance of S.A.L, and N.E. S.A.L, and N.E reviewed and supervised the writing of the manuscript. S.A.L was also responsible for the development of the main idea, managing the resources, and funding acquisition. All authors revised the manuscript and agreed to all its contents. Funding Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors agree to be published. Competing interests The authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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{ 'indexed': {'date-parts': [[2024, 9, 23]], 'date-time': '2024-09-23T20:29:44Z', 'timestamp': 1727123384255}, 'reference-count': 34, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2024, 9, 16]], 'date-time': '2024-09-16T00:00:00Z', 'timestamp': 1726444800000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2024, 9, 16]], 'date-time': '2024-09-16T00:00:00Z', 'timestamp': 1726444800000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/501100002386', 'name': 'Cairo University', 'doi-asserted-by': 'crossref', 'id': [{'id': '10.13039/501100002386', 'id-type': 'DOI', 'asserted-by': 'crossref'}]}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': 'AbstractDeveloping a potent antiviral agent to combat ' 'Coronavirus Disease-19 (COVID-19) is of critical importance as we may be at risk of the ' 'emergence of new virus strains or another pandemic recurrence. The interaction between the ' 'SARS-CoV-2 spike protein and Angiotensin Converting Enzyme 2 (ACE2) is the main ' 'protein-protein interaction (PPI) implicated in the virus entry into the host cells. ' 'Spike-ACE2 PPI represents a major target for drug intervention. We have repurposed a ' 'previously described protein-protein interaction detection method to be utilized as a drug ' 'screening assay. The assay was standardized using Chitosan nanoparticles (CNPs) as the drug ' 'and SARS-CoV-2 spike-ACE2 interaction as the PPI model. The assay was then used to screen ' 'four natural bioactive compounds: Curcumin (Cur), Gallic acid (GA), Quercetin (Q), and ' 'Silymarin (Sil), and their cytotoxicity was evaluated in vitro. Production of the spike ' 'protein and the evaluation of its activity in comparison to a standard commercial protein was ' 'part of our work as well. Here we describe a novel simple immunofluorescent screening assay ' 'to identify potential SARS-CoV-2 inhibitors that could assess the inhibitory effect of any ' 'ligand against any PPI.\n' ' Graphical Abstract', 'DOI': '10.1186/s13568-024-01739-8', 'type': 'journal-article', 'created': {'date-parts': [[2024, 9, 16]], 'date-time': '2024-09-16T16:03:19Z', 'timestamp': 1726502599000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors', 'prefix': '10.1186', 'volume': '14', 'author': [ {'given': 'Merna H.', 'family': 'Emam', 'sequence': 'first', 'affiliation': []}, {'given': 'Mohamed I.', 'family': 'Mahmoud', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nadia', 'family': 'El-Guendy', 'sequence': 'additional', 'affiliation': []}, { 'ORCID': 'http://orcid.org/0000-0003-1959-434X', 'authenticated-orcid': False, 'given': 'Samah A.', 'family': 'Loutfy', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2024, 9, 16]]}, 'reference': [ { 'key': '1739_CR1', 'doi-asserted-by': 'publisher', 'unstructured': 'Abdullah H, Ismail I, Suppian R, Nor Munirah Z (2023) Natural gallic ' 'acid and Methyl Gallate induces apoptosis in hela cells through ' 'regulation of intrinsic and extrinsic protein expression. Int J Mol Sci ' '24(10). https://doi.org/10.3390/ijms24108495', 'DOI': '10.3390/ijms24108495'}, { 'key': '1739_CR2', 'doi-asserted-by': 'publisher', 'unstructured': 'Ahamad S, Ali H, Secco I, Giacca M, Gupta D (2022) Anti-fungal drug ' 'Anidulafungin inhibits SARS-CoV-2 Spike-Induced Syncytia formation by ' 'Targeting ACE2-Spike Protein Interaction. Front Genet 13. ' 'https://doi.org/10.3389/fgene.2022.866474', 'DOI': '10.3389/fgene.2022.866474'}, { 'key': '1739_CR3', 'doi-asserted-by': 'publisher', 'unstructured': 'Al-Harrasi A, Behl T, Upadhyay T, Chigurupati S, Bhatt S, Sehgal A, ' 'Bhatia S, Singh S, Sharma N, Vijayabalan S Vasanth Raj Palanimuthu, ' 'Suprava Das, Rajwinder Kaur, Lotfi Aleya, and Simona Bungau. 2022. ' '‘Targeting Natural products against SARS-CoV-2’. Environ Sci Pollut Res ' '29(28):42404–42432. https://doi.org/10.1007/s11356-022-19770-2', 'DOI': '10.1007/s11356-022-19770-2'}, { 'issue': '10', 'key': '1739_CR4', 'doi-asserted-by': 'publisher', 'first-page': '1274', 'DOI': '10.1002/jcph.1874', 'volume': '61', 'author': 'S Assadiasl', 'year': '2021', 'unstructured': 'Assadiasl S, Fatahi Y, Mosharmovahed B, Mohebbi B, Mohammad Hossein ' 'Nicknam (2021) Baricitinib: from rheumatoid arthritis to COVID-19. J ' 'Clin Pharmacol 61(10):1274–1285. https://doi.org/10.1002/jcph.1874', 'journal-title': 'J Clin Pharmacol'}, { 'issue': '10', 'key': '1739_CR5', 'doi-asserted-by': 'publisher', 'first-page': '5215', 'DOI': '10.1002/fsn3.1858', 'volume': '8', 'author': 'F Babaei', 'year': '2020', 'unstructured': 'Babaei F, Marjan Nassiri-Asl, and Hossein Hosseinzadeh (2020) Curcumin ' '(a constituent of Turmeric): New Treatment option against COVID-19. Food ' 'Sci Nutr 8(10):5215–5227. https://doi.org/10.1002/fsn3.1858', 'journal-title': 'Food Sci Nutr'}, { 'key': '1739_CR6', 'doi-asserted-by': 'publisher', 'unstructured': 'Bizzoca M, Eleonora S, Leuci MD, Mignogna Eleonora Lo Muzio, Vito Carlo ' 'Alberto Caponio, and Lorenzo Lo Muzio. 2022. ‘Natural compounds may ' 'contribute in preventing SARS-CoV-2 infection: a narrative review’. Food ' 'Sci Hum Wellness 11(5):1134–1142. ' 'https://doi.org/10.1016/j.fshw.2022.04.005', 'DOI': '10.1016/j.fshw.2022.04.005'}, { 'issue': '6', 'key': '1739_CR7', 'doi-asserted-by': 'publisher', 'first-page': '1519', 'DOI': '10.1021/acsinfecdis.1c00070', 'volume': '7', 'author': 'D Bojadzic', 'year': '2021', 'unstructured': 'Bojadzic D, Alcazar O, Chen J, Chuang ST, Jose M, Condor Capcha LA, ' 'Shehadeh, and Peter Buchwald (2021) Small-molecule inhibitors of the ' 'Coronavirus Spike: ACE2 protein-protein Interaction as blockers of viral ' 'attachment and entry for SARS-CoV-2. ACS Infect Dis 7(6):1519–1534. ' 'https://doi.org/10.1021/acsinfecdis.1c00070', 'journal-title': 'ACS Infect Dis'}, { 'issue': '4', 'key': '1739_CR8', 'first-page': '2920', 'volume': '25', 'author': 'M Bozorgmanesh', 'year': '2021', 'unstructured': 'Bozorgmanesh M, Yousefifar Y, Jamalian M, Mahmoodiyeh B, Kamali A (2021) ' 'A review on common treatments for COVID-19 and Use of Tocilizumab ' '(ACTEMRA) in reducing effects of the Disease. Annals Romanian Soc Cell ' 'Biology 25(4):2920–2936', 'journal-title': 'Annals Romanian Soc Cell Biology'}, { 'issue': '27', 'key': '1739_CR9', 'doi-asserted-by': 'publisher', 'first-page': '16711', 'DOI': '10.1039/d1ra00644d', 'volume': '11', 'author': 'R Chakravarti', 'year': '2021', 'unstructured': 'Chakravarti R, Singh R, Ghosh A, Dey D, Sharma P, Velayutham R, Roy S, ' 'Dipanjan Ghosh (2021) A review on potential of Natural products in the ' 'management of COVID-19. RSC Adv 11(27):16711–16735. ' 'https://doi.org/10.1039/d1ra00644d', 'journal-title': 'RSC Adv'}, { 'key': '1739_CR10', 'unstructured': 'Emam MH, Ahmed I, Abdel-Salam Y, Moatasim MR, Gomaa, Nasra F, Abdel ' 'Fattah F, Ali HM, Alam El-Din A, Mostafa MA, Ali SA, Loutfy (2021) and ' 'Amal Kasry. ‘Development of a Newly Confirmatory Immunoassay to Evaluate ' 'Anti-Viral Activity of Chitosan Nanoparticles (Cnps) against SARS-CoV-2 ' 'Spike Protein’. in The annual conference of National Cancer Institute - ' 'Cairo University ‘Bridging Gaps in Oncology’. Cairo: Journal of the ' 'Egyptian National Cancer Institute'}, { 'issue': '25', 'key': '1739_CR11', 'doi-asserted-by': 'publisher', 'first-page': '16184', 'DOI': '10.1039/d2ra01321e', 'volume': '12', 'author': 'MH Emam', 'year': '2022', 'unstructured': 'Emam MH, Nageh H, Ali F, Taha M, ElShehaby HA, Amin R, Kamoun EA, Loutfy ' 'SA, and Amal Kasry (2022) Inhibition of SARS-CoV-2 spike protein entry ' 'using biologically modified Polyacrylonitrile nanofibers: in Vitro Study ' 'towards specific antiviral masks. RSC Adv 12(25):16184–16193. ' 'https://doi.org/10.1039/d2ra01321e', 'journal-title': 'RSC Adv'}, { 'issue': '2', 'key': '1739_CR12', 'doi-asserted-by': 'publisher', 'first-page': '619', 'DOI': '10.3892/etm.2015.2923', 'volume': '11', 'author': 'M Govea-Salas', 'year': '2016', 'unstructured': 'Govea-Salas M, Rivas-Estilla AM, Rodríguez-Herrera R, Lozano-Sepúlveda ' 'SA, Aguilar-Gonzalez CN, Zugasti-Cruz A, Salas-Villalobos TB, Jesus ' 'Antonio Morlett-Chávez (2016) Gallic acid decreases Hepatitis C Virus ' 'expression through its antioxidant capacity. Experimental Therapeutic ' 'Med 11(2):619–624. https://doi.org/10.3892/etm.2015.2923', 'journal-title': 'Experimental Therapeutic Med'}, { 'key': '1739_CR13', 'doi-asserted-by': 'publisher', 'unstructured': 'Hiremath, Shridhar HD, Vinay Kumar M, Nandan M, Mantesh KS, Shankarappa ' 'V, Venkataravanappa CR, Jahir, Basha, Lakshminarayana CN (2021) Reddy. ' '‘In Silico Docking Analysis Revealed the Potential of Phytochemicals ' 'Present in Phyllanthus Amarus and Andrographis Paniculata, Used in ' 'Ayurveda Medicine in Inhibiting SARS-CoV-2’. 3 Biotech 11(2). ' 'https://doi.org/10.1007/s13205-020-02578-7', 'DOI': '10.1007/s13205-020-02578-7'}, { 'key': '1739_CR14', 'doi-asserted-by': 'publisher', 'unstructured': 'Jadel, Müller, Kratz Carla Regina Andrighetti-Fröhner, Paulo César Leal, ' 'Ricardo José Nunes, Rosendo Augusto Yunes, Edward Trybala, Tomas ' 'Bergström, Célia Regina Monte Barardi, and Cláudia Maria Oliveira ' 'Simões. 2008. ‘Evaluation of Anti-HSV-2 activity of gallic acid and ' 'Pentyl Gallate’. Biol Pharm Bull 31(5):903–907. ' 'https://doi.org/10.1248/bpb.31.903', 'DOI': '10.1248/bpb.31.903'}, { 'issue': '4', 'key': '1739_CR15', 'doi-asserted-by': 'publisher', 'first-page': '416', 'DOI': '10.1165/rcmb.2020-0322PS', 'volume': '64', 'author': 'H Jia', 'year': '2021', 'unstructured': 'Jia H, Neptune E, Cui H (2021) Targeting ACE2 for COVID-19 therapy: ' 'opportunities and challenges. Am J Respir Cell Mol Biol 64(4):416–425. ' 'https://doi.org/10.1165/rcmb.2020-0322PS', 'journal-title': 'Am J Respir Cell Mol Biol'}, { 'issue': '1', 'key': '1739_CR16', 'first-page': '63', 'volume': '2', 'author': 'N Khan', 'year': '2021', 'unstructured': 'Khan N, Chen X, Geiger JD (2021) Possible therapeutic use of natural ' 'compounds against COVID-19. J Cell Signal 2(1):63–79', 'journal-title': 'J Cell Signal'}, { 'key': '1739_CR17', 'doi-asserted-by': 'publisher', 'unstructured': 'Lai C-C, Po‐Ren H (2023) Coronavirus Disease 2019 Rebounds following ' 'Nirmatrelvir/Ritonavir Treatment. J Med Virol 95(2). ' 'https://doi.org/10.1002/jmv.28430', 'DOI': '10.1002/jmv.28430'}, { 'issue': '13', 'key': '1739_CR18', 'doi-asserted-by': 'publisher', 'first-page': '1355', 'DOI': '10.1007/s40265-020-01378-w', 'volume': '80', 'author': 'YN Lamb', 'year': '2020', 'unstructured': 'Lamb YN (2020) Remdesivir: first approval. Drugs 80(13):1355–1363. ' 'https://doi.org/10.1007/s40265-020-01378-w', 'journal-title': 'Drugs'}, { 'key': '1739_CR19', 'doi-asserted-by': 'publisher', 'unstructured': 'Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H, Yulong Yin ' '(2016) Quercetin, inflammation and immunity. Nutrients 8(3). ' 'https://doi.org/10.3390/nu8030167', 'DOI': '10.3390/nu8030167'}, { 'key': '1739_CR21', 'doi-asserted-by': 'publisher', 'unstructured': 'Loutfy SA, Ahmed I, Abdel-Salam Y, Moatasim MR, Gomaa, Nasra F, Abdel ' 'Fattah MH, Emam F, Ali HA, ElShehaby, Eman A, Ragab HM. Alam El-Din, ' 'Ahmed Mostafa, Ali MA, and Amal Kasry (2022b). ‘Antiviral Activity of ' 'Chitosan Nanoparticles Encapsulating Silymarin (Sil-CNPs) against ' 'SARS-CoV-2 (in Silicoin Vitro Study)’. RSC Advances 12(25):15775–86. ' 'https://doi.org/10.1039/d2ra00905f', 'DOI': '10.1039/d2ra00905f'}, { 'key': '1739_CR22', 'doi-asserted-by': 'publisher', 'unstructured': 'Low Z, Xuan BM, OuYong P, Hassandarvish CL, Poh, and Babu Ramanathan ' '(2021) Antiviral activity of silymarin and Baicalein against Dengue ' 'Virus. Sci Rep 11(1). https://doi.org/10.1038/s41598-021-98949-y', 'DOI': '10.1038/s41598-021-98949-y'}, { 'key': '1739_CR23', 'doi-asserted-by': 'publisher', 'unstructured': 'Marín-Palma D, Tabares-Guevara JH, Zapata-Cardona MaríaI, Flórez-álvarez ' 'L, Yepes LM, Maria T, Rugeles JC, Hernandez (2021) and Natalia A. ' 'Taborda. ‘Curcumin Inhibits in Vitro Sars-Cov-2 Infection in Vero E6 ' 'Cells through Multiple Antiviral Mechanisms’. Molecules 26(22). ' 'https://doi.org/10.3390/molecules26226900', 'DOI': '10.3390/molecules26226900'}, { 'key': '1739_CR24', 'doi-asserted-by': 'crossref', 'unstructured': 'Mosmann T (1983) Rapid Colorimetric Assay for Cellular Growth and ' 'Survival: Application to Proliferation and Cytotoxicity Assays. Vol. 65', 'DOI': '10.1016/0022-1759(83)90303-4'}, { 'key': '1739_CR25', 'doi-asserted-by': 'publisher', 'unstructured': 'Murakami N, Hayden R, Hills T, Al-Samkari H, Casey J, Sorbo LD, Lawler ' 'PR, Sise ME (2023) and David E. Leaf. ‘Therapeutic Advances in ' 'COVID-19’. Nature Reviews Nephrology 19(1):38–52. ' 'https://doi.org/10.1038/s41581-022-00642-4', 'DOI': '10.1038/s41581-022-00642-4'}, { 'key': '1739_CR26', 'doi-asserted-by': 'publisher', 'unstructured': 'Ortiz-Andrade R, Jesús Alfredo Araujo-León, Amanda Sánchez-Recillas, ' 'Gabriel Navarrete-Vazquez, Avel Adolfo González-Sánchez, Sergio ' 'Hidalgo-Figueroa, Ángel Josabad Alonso-Castro, Irma Aranda-González, ' 'Emanuel Hernández-Núñez, Tania Isolina Coral-Martínez, Juan Carlos ' 'Sánchez-Salgado, Victor Yáñez-Pérez, and, Lucio-Garcia MA (2020) ' '‘Toxicological Screening of Four Bioactive Citroflavonoids: In Vitro, In ' 'Vivo, and In Silico Approaches’. Molecules 25(24). ' 'https://doi.org/10.3390/MOLECULES25245959', 'DOI': '10.3390/MOLECULES25245959'}, { 'key': '1739_CR27', 'doi-asserted-by': 'publisher', 'first-page': '3518', 'DOI': '10.1016/j.csbj.2020.11.010', 'volume': '18', 'author': 'B Pan', 'year': '2020', 'unstructured': 'Pan B, Fang S, Zhang J, Pan Y, Liu H, Wang Y, Li M, Liren Liu (2020) ' 'Chinese Herbal compounds against SARS-CoV-2: Puerarin and quercetin ' 'impair the binding of viral S-Protein to ACE2 receptor. Comput Struct ' 'Biotechnol J 18:3518–3527. https://doi.org/10.1016/j.csbj.2020.11.010', 'journal-title': 'Comput Struct Biotechnol J'}, { 'key': '1739_CR28', 'doi-asserted-by': 'publisher', 'unstructured': 'Rattis BAC, Simone G, Ramos, Celes MRN (2021) Curcumin as a potential ' 'treatment for COVID-19. Front Pharmacol 12. ' 'https://doi.org/10.3389/fphar.2021.675287', 'DOI': '10.3389/fphar.2021.675287'}, { 'issue': '1', 'key': '1739_CR29', 'doi-asserted-by': 'publisher', 'first-page': '165', 'DOI': '10.1093/cid/ciac180', 'volume': '76', 'author': 'LD Saravolatz', 'year': '2023', 'unstructured': 'Saravolatz LD, Depcinski S, Sharma M (2023) Molnupiravir and ' 'Nirmatrelvir-Ritonavir: oral coronavirus Disease 2019 antiviral drugs. ' 'Clin Infect Dis 76(1):165–171. https://doi.org/10.1093/cid/ciac180', 'journal-title': 'Clin Infect Dis'}, { 'issue': '6', 'key': '1739_CR30', 'doi-asserted-by': 'publisher', 'first-page': '867', 'DOI': '10.1007/s00408-020-00408-4', 'volume': '198', 'author': 'F Scialo', 'year': '2020', 'unstructured': 'Scialo F, Daniele A, Amato F, Pastore L, Matera MG, Cazzola M, Castaldo ' 'G, Bianco A (2020) ACE2: the major cell entry receptor for SARS-CoV-2. ' 'Lung 198(6):867–877. https://doi.org/10.1007/s00408-020-00408-4', 'journal-title': 'Lung'}, { 'key': '1739_CR31', 'doi-asserted-by': 'publisher', 'unstructured': 'Soni V, Kumar A, Mehta YK, Ratre AK, Tiwari A, Amit RP, Singh Subash ' 'Chandra Sonkar, Navaneet Chaturvedi, Dhananjay Shukla, and Naveen Kumar ' 'Vishvakarma. 2020. ‘Curcumin, a traditional spice component, can hold ' 'the Promise against COVID-19?’. Eur J Pharmacol 886. ' 'https://doi.org/10.1016/j.ejphar.2020.173551', 'DOI': '10.1016/j.ejphar.2020.173551'}, { 'issue': '18', 'key': '1739_CR32', 'doi-asserted-by': 'publisher', 'first-page': '12041', 'DOI': '10.1021/acs.joc.2c01047', 'volume': '87', 'author': 'F Tedesco', 'year': '2022', 'unstructured': 'Tedesco F, Calugi L, Lenci E, Trabocchi A (2022) Peptidomimetic ' 'Small-Molecule inhibitors of 3CLPro Activity and Spike-ACE2 Interaction: ' 'toward dual-action molecules against Coronavirus infections. J Org Chem ' '87(18):12041–12051. https://doi.org/10.1021/acs.joc.2c01047', 'journal-title': 'J Org Chem'}, { 'key': '1739_CR33', 'doi-asserted-by': 'publisher', 'unstructured': 'Vahedian-Azimi A, Abbasifard M, Rahimi-Bashar F, Guest PC, Majeed M, ' 'Mohammadi A, Banach M Tannaz Jamialahmadi, and Amirhossein Sahebkar. ' '2022. ‘Effectiveness of Curcumin on outcomes of hospitalized COVID-19 ' 'patients: a systematic review of clinical trials’. Nutrients 14(2). ' 'https://doi.org/10.3390/nu14020256', 'DOI': '10.3390/nu14020256'}, { 'key': '1739_CR34', 'doi-asserted-by': 'crossref', 'unstructured': 'Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, Graham ' 'BS, Mclellan JS (2019) Cryo-EM Structure of the 2019-NCoV Spike in the ' 'Prefusion Conformation', 'DOI': '10.1101/2020.02.11.944462'}, { 'key': '1739_CR35', 'doi-asserted-by': 'publisher', 'unstructured': 'Xu D, Wang MJHYQ, Yuan Lu C (2019) Antioxidant activities of Quercetin ' 'and its complexes for Medicinal Application. Molecules 24(6). ' 'https://doi.org/10.3390/molecules24061123', 'DOI': '10.3390/molecules24061123'}], 'container-title': 'AMB Express', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s13568-024-01739-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s13568-024-01739-8/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s13568-024-01739-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 9, 16]], 'date-time': '2024-09-16T16:12:52Z', 'timestamp': 1726503172000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://amb-express.springeropen.com/articles/10.1186/s13568-024-01739-8'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 9, 16]]}, 'references-count': 34, 'journal-issue': {'issue': '1', 'published-online': {'date-parts': [[2024, 12]]}}, 'alternative-id': ['1739'], 'URL': 'http://dx.doi.org/10.1186/s13568-024-01739-8', 'relation': {}, 'ISSN': ['2191-0855'], 'subject': [], 'container-title-short': 'AMB Expr', 'published': {'date-parts': [[2024, 9, 16]]}, 'assertion': [ { 'value': '7 February 2024', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '4 July 2024', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '16 September 2024', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'Not applicable.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'All authors agree to be published.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The authors declare no competing interests.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '104'}

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