Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites

Fam et al., Scientific Reports, doi:10.1038/s41598-023-31764-9, Apr 2023
Quercetin for COVID-19
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In vitro study showing that adamantane derivatives and six out of ten tested polyphenols including curcumin and quercetin inhibited the SARS-CoV-2 viroporin ORF3a, which contributes to viral pathogenicity and cytotoxicity. Authors used cell viability assays and patch-clamp electrophysiology to test rimantadine, amantadine, and ten phenolic compounds against recombinant ORF3a expressed in HEK293 cells. Rimantadine, amantadine, epigallocatechin gallate (EGCG), quercetin, nobiletin, kaempferol, curcumin and resveratrol inhibited ORF3a activity, while apigenin, genistein, naringenin and 6-gingerol were inactive. Inhibitory potency of flavonoids appeared to correlate with the pattern of OH groups on the chromone ring system.
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
87 preclinical studies support the efficacy of quercetin for COVID-19:
52 in silico studies1-52
29 in vitro studies1,3,4,6-8,11,21,26,28,32,49,53-69
6 in vivo animal studies11,26,61,64,70,71
In silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,8,9,15,16,29,31,32,34,37,45,46,48,49,72 (and specifically the receptor binding domainB,5), MproC,4,5,8,9,13,15,17,19,21,23,25,27,30,31,34,37,41,43-45,49-52,69, RNA-dependent RNA polymeraseD,5,7-9,15,39, PLproE,9,44,52, ACE2F,24,29,30,34,35,44,48, TMPRSS2G,29, nucleocapsidH,9, helicaseI,9,36,41, endoribonucleaseJ,46, NSP16/10K,12, cathepsin LL,33, Wnt-3M,29, FZDN,29, LRP6O,29, ezrinP,47, ADRPQ,45, NRP1R,48, EP300S,22, PTGS2T,30, HSP90AA1U,22,30, matrix metalloproteinase 9V,38, IL-6W,28,42, IL-10X,28, VEGFAY,42, and RELAZ,42 proteins, and inhibition of spike-ACE2 interactionAA,6. In vitro studies demonstrate inhibition of the MproC,21,55,60,68 protein, and inhibition of spike-ACE2 interactionAA,56. In vitro studies demonstrate efficacy in Calu-3AB,59, A549AC,28, HEK293-ACE2+AD,67, Huh-7AE,32, Caco-2AF,58, Vero E6AG,26,49,58, mTECAH,61, RAW264.7AI,61, and HLMECAJ,6 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAK,64, db/db miceAL,61,71, BALB/c miceAM,70, and rats26. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice70, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages11, may block ACE2-spike interaction and NLRP3 inflammasome, limiting viral entry and inflammation2, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity63.
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Study covers quercetin and curcumin.
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. 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.
h. 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.
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 endoribonuclease, also known as NendoU or nsp15, cleaves specific sequences in viral RNA which may help the virus evade detection by the host immune system. Inhibition may hinder the virus's ability to mask itself from the immune system, facilitating a stronger immune response.
k. The NSP16/10 complex consists of non-structural proteins 16 and 10, forming a 2'-O-methyltransferase that modifies the viral RNA cap structure. This modification helps the virus evade host immune detection by mimicking host mRNA, making NSP16/10 a promising antiviral target.
l. Cathepsin L is a host lysosomal cysteine protease that can prime the spike protein through an alternative pathway when TMPRSS2 is unavailable. Dual targeting of cathepsin L and TMPRSS2 may maximize disruption of alternative pathways for virus entry.
m. Wingless-related integration site (Wnt) ligand 3 is a host signaling molecule that activates the Wnt signaling pathway, which is important in development, cell growth, and tissue repair. Some studies suggest that SARS-CoV-2 infection may interfere with the Wnt signaling pathway, and that Wnt3a is involved in SARS-CoV-2 entry.
n. The frizzled (FZD) receptor is a host transmembrane receptor that binds Wnt ligands, initiating the Wnt signaling cascade. FZD serves as a co-receptor, along with ACE2, in some proposed mechanisms of SARS-CoV-2 infection. The virus may take advantage of this pathway as an alternative entry route.
o. Low-density lipoprotein receptor-related protein 6 is a cell surface co-receptor essential for Wnt signaling. LRP6 acts in tandem with FZD for signal transduction and has been discussed as a potential co-receptor for SARS-CoV-2 entry.
p. The ezrin protein links the cell membrane to the cytoskeleton (the cell's internal support structure) and plays a role in cell shape, movement, adhesion, and signaling. Drugs that occupy the same spot on ezrin where the viral spike protein would bind may hindering viral attachment, and drug binding could further stabilize ezrin, strengthening its potential natural capacity to impede viral fusion and entry.
q. The Adipocyte Differentiation-Related Protein (ADRP, also known as Perilipin 2 or PLIN2) is a lipid droplet protein regulating the storage and breakdown of fats in cells. SARS-CoV-2 may hijack the lipid handling machinery of host cells and ADRP may play a role in this process. Disrupting ADRP's interaction with the virus may hinder the virus's ability to use lipids for replication and assembly.
r. Neuropilin-1 (NRP1) is a cell surface receptor with roles in blood vessel development, nerve cell guidance, and immune responses. NRP1 may function as a co-receptor for SARS-CoV-2, facilitating viral entry into cells. Blocking NRP1 may disrupt an alternative route of viral entry.
s. EP300 (E1A Binding Protein P300) is a transcriptional coactivator involved in several cellular processes, including growth, differentiation, and apoptosis, through its acetyltransferase activity that modifies histones and non-histone proteins. EP300 facilitates viral entry into cells and upregulates inflammatory cytokine production.
t. Prostaglandin G/H synthase 2 (PTGS2, also known as COX-2) is an enzyme crucial for the production of inflammatory molecules called prostaglandins. PTGS2 plays a role in the inflammatory response that can become severe in COVID-19 and inhibitors (like some NSAIDs) may have benefits in dampening harmful inflammation, but note that prostaglandins have diverse physiological functions.
u. Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) is a chaperone protein that helps other proteins fold correctly and maintains their stability. HSP90AA1 plays roles in cell signaling, survival, and immune responses. HSP90AA1 may interact with numerous viral proteins, but note that it has diverse physiological functions.
v. Matrix metalloproteinase 9 (MMP9), also called gelatinase B, is a zinc-dependent enzyme that breaks down collagen and other components of the extracellular matrix. MMP9 levels increase in severe COVID-19. Overactive MMP9 can damage lung tissue and worsen inflammation. Inhibition of MMP9 may prevent excessive tissue damage and help regulate the inflammatory response.
w. The interleukin-6 (IL-6) pro-inflammatory cytokine (signaling molecule) has a complex role in the immune response and may trigger and perpetuate inflammation. Elevated IL-6 levels are associated with severe COVID-19 cases and cytokine storm. Anti-IL-6 therapies may be beneficial in reducing excessive inflammation in severe COVID-19 cases.
x. The interleukin-10 (IL-10) anti-inflammatory cytokine helps regulate and dampen immune responses, preventing excessive inflammation. IL-10 levels can also be elevated in severe COVID-19. IL-10 could either help control harmful inflammation or potentially contribute to immune suppression.
y. Vascular Endothelial Growth Factor A (VEGFA) promotes the growth of new blood vessels (angiogenesis) and has roles in inflammation and immune responses. VEGFA may contribute to blood vessel leakiness and excessive inflammation associated with severe COVID-19.
z. RELA is a transcription factor subunit of NF-kB and is a key regulator of inflammation, driving pro-inflammatory gene expression. SARS-CoV-2 may hijack and modulate NF-kB pathways.
aa. 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.
ab. 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.
ac. 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.
ad. HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.
ae. Huh-7 cells were derived from a liver tumor (hepatoma).
af. Caco-2 cells come from a colorectal adenocarcinoma (cancer). They are valued for their ability to form a polarized cell layer with properties similar to the intestinal lining.
ag. 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.
ah. mTEC is a mouse tubular epithelial cell line.
ai. RAW264.7 is a mouse macrophage cell line.
aj. HLMEC (Human Lung Microvascular Endothelial Cells) are primary endothelial cells derived from the lung microvasculature. They are used to study endothelial function, inflammation, and viral interactions, particularly in the context of lung infections such as SARS-CoV-2. HLMEC express ACE2 and are susceptible to SARS-CoV-2 infection, making them a relevant model for studying viral entry and endothelial responses in the lung.
ak. A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
al. A mouse model of obesity and severe insulin resistance leading to type 2 diabetes due to a mutation in the leptin receptor gene that impairs satiety signaling.
am. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
Fam et al., 1 Apr 2023, peer-reviewed, 5 authors. Contact: ulrike.breitinger@guc.edu.eg.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites
Marina Sherif Fam, Christine Adel Sedky, Nancy Osama Turky, Hans-Georg Breitinger, Ulrike Breitinger
Scientific Reports, doi:10.1038/s41598-023-31764-9
SARS-CoV-2 has been responsible for the major worldwide pandemic of COVID-19. Despite the enormous success of vaccination campaigns, virus infections are still prevalent and effective antiviral therapies are urgently needed. Viroporins are essential for virus replication and release, and are thus promising therapeutic targets. Here, we studied the expression and function of recombinant ORF3a viroporin of SARS-CoV-2 using a combination of cell viability assays and patch-clamp electrophysiology. ORF3a was expressed in HEK293 cells and transport to the plasma membrane verified by a dot blot assay. Incorporation of a membrane-directing signal peptide increased plasma membrane expression. Cell viability tests were carried out to measure cell damage associated with ORF3a activity, and voltage-clamp recordings verified its channel activity. The classical viroporin inhibitors amantadine and rimantadine inhibited ORF3a channels. A series of ten flavonoids and polyphenolics were studied. Kaempferol, quercetin, epigallocatechin gallate, nobiletin, resveratrol and curcumin were ORF3a inhibitors, with IC 50 values ranging between 1 and 6 µM, while 6-gingerol, apigenin, naringenin and genistein were inactive. For flavonoids, inhibitory activity could be related to the pattern of OH groups on the chromone ring system. Thus, the ORF3a viroporin of SARS-CoV-2 may indeed be a promising target for antiviral drugs. Coronaviruses (CoVs) belong to the order Nidovirales, family Coronaviridae, and subfamily Coronavirinae 1 . They are subdivided into four different genera named α-, β-, γ-, and δ-CoVs 2 . Coronaviruses have been known to infect humans 2-4 , usually causing mild respiratory infections such as a common cold. However, in the past 20 years, two major outbreaks occurred due to crossover of animal β-coronavirus to humans 5 . In 2002-03 humans were infected by bat coronavirus resulting in severe acute respiratory syndrome coronavirus (SARS-CoV) and in 2019, a novel coronavirus of bat origin that had spread to humans, had been discovered in Wuhan, China 6 . This new virus, named SARS-CoV-2, is a member of the β-coronavirus family and is responsible for the ongoing pandemic of COVID-19 1, 7, 8 . SARS-CoVs are enveloped, positive sense single-stranded RNA viruses, with a genome of approximately 30 kb arranged into 14 open reading frames (ORF) encoding 31 proteins [8] [9] [10] [11] . Spike (S), envelope (E), membrane (M) and nucleoprotein (N) are the four structural proteins forming the virus capsid. The S protein binds to the host receptor through the receptor-binding domain in the S1 subunit, while S2 subunit is responsible for membrane fusion 8 . The E protein belongs to the class of viroporins, integral membrane proteins functioning as ion channels and promoting virus release. It was found to be expressed in the ER and the Golgi apparatus forming an ion channel allowing the efflux of cations Na + , K + and Ca 2+ , and is required for pathogenesis and..
Author contributions M.S.F.: design of work, data acquisition and analysis, interpretation of data, revising the manuscript. C.A.S.: data acquisition and analysis, interpretation of data, revising the manuscript. N.O.T.: data acquisition and analysis, interpretation of data, revising the manuscript. H.G.B.: conception, design of work, data acquisition and analysis, interpretation of data, drafting and revising the manuscript. U.B.: conception, design of work, data acquisition and analysis, interpretation of data, drafting, writing and revising the manuscript. All authors have read and approved the submitted manuscript. Competing interests The authors declare no competing interests.
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DOI record: { "DOI": "10.1038/s41598-023-31764-9", "ISSN": [ "2045-2322" ], "URL": "http://dx.doi.org/10.1038/s41598-023-31764-9", "abstract": "<jats:title>Abstract</jats:title><jats:p>SARS-CoV-2 has been responsible for the major worldwide pandemic of COVID-19. Despite the enormous success of vaccination campaigns, virus infections are still prevalent and effective antiviral therapies are urgently needed. Viroporins are essential for virus replication and release, and are thus promising therapeutic targets. Here, we studied the expression and function of recombinant ORF3a viroporin of SARS-CoV-2 using a combination of cell viability assays and patch-clamp electrophysiology. ORF3a was expressed in HEK293 cells and transport to the plasma membrane verified by a dot blot assay. Incorporation of a membrane-directing signal peptide increased plasma membrane expression. Cell viability tests were carried out to measure cell damage associated with ORF3a activity, and voltage-clamp recordings verified its channel activity. The classical viroporin inhibitors amantadine and rimantadine inhibited ORF3a channels. A series of ten flavonoids and polyphenolics were studied. Kaempferol, quercetin, epigallocatechin gallate, nobiletin, resveratrol and curcumin were ORF3a inhibitors, with IC<jats:sub>50</jats:sub> values ranging between 1 and 6 µM, while 6-gingerol, apigenin, naringenin and genistein were inactive. For flavonoids, inhibitory activity could be related to the pattern of OH groups on the chromone ring system. Thus, the ORF3a viroporin of SARS-CoV-2 may indeed be a promising target for antiviral drugs.</jats:p>", "alternative-id": [ "31764" ], "article-number": "5328", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "28 September 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "16 March 2023" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "1 April 2023" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "The authors declare no competing interests." } ], "author": [ { "affiliation": [], "family": "Fam", "given": "Marina Sherif", "sequence": "first" }, { "affiliation": [], "family": "Sedky", "given": "Christine Adel", "sequence": "additional" }, { "affiliation": [], "family": "Turky", "given": "Nancy Osama", "sequence": "additional" }, { "affiliation": [], "family": "Breitinger", "given": "Hans-Georg", "sequence": "additional" }, { "affiliation": [], "family": "Breitinger", "given": "Ulrike", "sequence": "additional" } ], "container-title": "Scientific Reports", "container-title-short": "Sci Rep", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2023, 4, 3 ] ], "date-time": "2023-04-03T05:50:55Z", "timestamp": 1680501055000 }, "deposited": { "date-parts": [ [ 2023, 4, 3 ] ], "date-time": "2023-04-03T05:58:06Z", "timestamp": 1680501486000 }, "funder": [ { "DOI": "10.13039/501100003009", "award": [ "45420" ], "doi-asserted-by": "publisher", "name": "Science and Technology Development Fund" }, { "DOI": "10.13039/501100007637", "doi-asserted-by": "crossref", "name": "German University in Cairo" } ], "indexed": { "date-parts": [ [ 2023, 4, 4 ] ], "date-time": "2023-04-04T05:31:46Z", "timestamp": 1680586306786 }, "is-referenced-by-count": 0, "issue": "1", "issued": { "date-parts": [ [ 2023, 4, 1 ] ] }, "journal-issue": { "issue": "1", "published-online": { "date-parts": [ [ 2023, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 4, 1 ] ], "date-time": "2023-04-01T00:00:00Z", "timestamp": 1680307200000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 4, 1 ] ], "date-time": "2023-04-01T00:00:00Z", "timestamp": 1680307200000 } } ], "link": [ { "URL": "https://www.nature.com/articles/s41598-023-31764-9.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41598-023-31764-9", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41598-023-31764-9.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2023, 4, 1 ] ] }, "published-online": { "date-parts": [ [ 2023, 4, 1 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.1038/s41564-020-0695-z", "author": "AE Gorbalenya", "doi-asserted-by": "publisher", "first-page": "536", "issue": "4", "journal-title": "Nat. 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Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.
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