Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors
et al., AMB Express, doi:10.1186/s13568-024-01739-8, Sep 2024
Curcumin for COVID-19
16th treatment shown to reduce risk in
February 2021, now with p = 0.0000000061 from 28 studies.
No treatment is 100% effective. Protocols
combine treatments.
6,200+ studies for
200+ treatments. c19early.org
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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.
59 preclinical studies support the efficacy of curcumin for COVID-19:
In silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,4,5,10,15,17,23,26 (and specifically the receptor binding domainB,1,3,13,16,19 ), MproC,3-5,10,12,14-16,18,19,21,24,26,27,29,46 , RNA-dependent RNA polymeraseD,3-5,16,25 , PLproE,5, ACE2F,1,17,18,20 , nucleocapsidG,11,28 , nsp10H,28, and helicaseI,34 proteins, and inhibition of spike-ACE2 interactionJ,2.
In vitro studies demonstrate inhibition of the spikeA,39 (and specifically the receptor binding domainB,49), MproC,22,39,46,48 , ACE2F,49, and TMPRSS2K,49 proteins, and inhibition of spike-ACE2 interactionJ,2,32 .
In vitro studies demonstrate efficacy in Calu-3L,47, A549M,39, 293TN,6, HEK293-hACE2O,22,37 , 293T/hACE2/TMPRSS2P,38, Vero E6Q,12,16,26,37,39,41,43,45,47 , and SH-SY5YR,36 cells.
Curcumin decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells45, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress6, 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 fibroblasts33, 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 variants13, lowers ACE2 and STAT3, curbing lung inflammation and ARDS in preclinical COVID-19 models30, inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity40, has direct virucidal action by disrupting viral envelope integrity42, and can function as a photosensitizer in photodynamic therapy to generate reactive oxygen species that damage the virus42.
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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.
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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.
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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 Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro 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.
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.
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.
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.
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.
Establishment of in-house assay for screening of anti-SARS-CoV-2 protein inhibitors
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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DOI record:
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"DOI": "10.1186/s13568-024-01739-8",
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"URL": "http://dx.doi.org/10.1186/s13568-024-01739-8",
"abstract": "<jats:title>Abstract</jats:title><jats:p>Developing 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.</jats:p>\n <jats:p><jats:bold>Graphical Abstract</jats:bold></jats:p>",
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