PMC:7441788 / 7499-10485 JSON TXT

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LitCovid-PD-FMA-UBERON

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-sample-MedDRA

{"project":"LitCovid-sample-MedDRA","denotations":[{"id":"T4","span":{"begin":197,"end":226},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T5","span":{"begin":330,"end":343},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"},{"id":"T6","span":{"begin":1756,"end":1785},"obj":"http://purl.bioontology.org/ontology/MEDDRA/10022891"}],"attributes":[{"id":"A6","pred":"meddra_id","subj":"T6","obj":"http://purl.bioontology.org/ontology/MEDDRA/10050289"},{"id":"A5","pred":"meddra_id","subj":"T5","obj":"http://purl.bioontology.org/ontology/MEDDRA/10062026"},{"id":"A4","pred":"meddra_id","subj":"T4","obj":"http://purl.bioontology.org/ontology/MEDDRA/10050289"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

LitCovid-sample-CHEBI

LitCovid-sample-PD-NCBITaxon

{"project":"LitCovid-sample-PD-NCBITaxon","denotations":[{"id":"T68","span":{"begin":67,"end":77},"obj":"Species"},{"id":"T69","span":{"begin":415,"end":425},"obj":"Species"},{"id":"T70","span":{"begin":539,"end":547},"obj":"Species"},{"id":"T71","span":{"begin":919,"end":923},"obj":"Species"},{"id":"T72","span":{"begin":1193,"end":1201},"obj":"Species"},{"id":"T73","span":{"begin":1789,"end":1797},"obj":"Species"},{"id":"T74","span":{"begin":1799,"end":1823},"obj":"Species"},{"id":"T75","span":{"begin":2282,"end":2289},"obj":"Species"},{"id":"T76","span":{"begin":2347,"end":2355},"obj":"Species"},{"id":"T77","span":{"begin":2365,"end":2374},"obj":"Species"},{"id":"T78","span":{"begin":2437,"end":2447},"obj":"Species"}],"attributes":[{"id":"A69","pred":"ncbi_taxonomy_id","subj":"T69","obj":"NCBItxid:2697049"},{"id":"A78","pred":"ncbi_taxonomy_id","subj":"T78","obj":"NCBItxid:2697049"},{"id":"A70","pred":"ncbi_taxonomy_id","subj":"T70","obj":"NCBItxid:694009"},{"id":"A75","pred":"ncbi_taxonomy_id","subj":"T75","obj":"NCBItxid:10239"},{"id":"A73","pred":"ncbi_taxonomy_id","subj":"T73","obj":"NCBItxid:2697049"},{"id":"A76","pred":"ncbi_taxonomy_id","subj":"T76","obj":"NCBItxid:694009"},{"id":"A77","pred":"ncbi_taxonomy_id","subj":"T77","obj":"NCBItxid:31631"},{"id":"A74","pred":"ncbi_taxonomy_id","subj":"T74","obj":"NCBItxid:2697049"},{"id":"A68","pred":"ncbi_taxonomy_id","subj":"T68","obj":"NCBItxid:2697049"},{"id":"A72","pred":"ncbi_taxonomy_id","subj":"T72","obj":"NCBItxid:2697049"},{"id":"A71","pred":"ncbi_taxonomy_id","subj":"T71","obj":"NCBItxid:694009"}],"namespaces":[{"prefix":"NCBItxid","uri":"http://purl.bioontology.org/ontology/NCBITAXON/"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

LitCovid-sample-sentences

{"project":"LitCovid-sample-sentences","denotations":[{"id":"T62","span":{"begin":0,"end":6},"obj":"Sentence"},{"id":"T63","span":{"begin":8,"end":49},"obj":"Sentence"},{"id":"T64","span":{"begin":50,"end":141},"obj":"Sentence"},{"id":"T65","span":{"begin":142,"end":325},"obj":"Sentence"},{"id":"T66","span":{"begin":326,"end":714},"obj":"Sentence"},{"id":"T67","span":{"begin":715,"end":988},"obj":"Sentence"},{"id":"T68","span":{"begin":989,"end":998},"obj":"Sentence"},{"id":"T69","span":{"begin":999,"end":1117},"obj":"Sentence"},{"id":"T70","span":{"begin":1118,"end":1749},"obj":"Sentence"},{"id":"T71","span":{"begin":1750,"end":2100},"obj":"Sentence"},{"id":"T72","span":{"begin":2101,"end":2386},"obj":"Sentence"},{"id":"T73","span":{"begin":2387,"end":2585},"obj":"Sentence"},{"id":"T74","span":{"begin":2586,"end":2726},"obj":"Sentence"},{"id":"T75","span":{"begin":2727,"end":2834},"obj":"Sentence"},{"id":"T76","span":{"begin":2835,"end":2986},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

LitCovid-sample-Pubtator

LitCovid-sample-UniProt

LitCovid-sample-PD-IDO

LitCovid-sample-PD-FMA

LitCovid-sample-PD-GO-BP-0

LitCovid-sample-PD-MONDO

LitCovid-sample-PD-HP

{"project":"LitCovid-sample-PD-HP","denotations":[{"id":"T8","span":{"begin":2076,"end":2081},"obj":"Phenotype"}],"attributes":[{"id":"A8","pred":"hp_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

LitCovid-sample-GO-BP

LitCovid-PD-GO-BP

LitCovid-PubTator

LitCovid-sentences

{"project":"LitCovid-sentences","denotations":[{"id":"T62","span":{"begin":0,"end":6},"obj":"Sentence"},{"id":"T63","span":{"begin":8,"end":49},"obj":"Sentence"},{"id":"T64","span":{"begin":50,"end":141},"obj":"Sentence"},{"id":"T65","span":{"begin":142,"end":325},"obj":"Sentence"},{"id":"T66","span":{"begin":326,"end":714},"obj":"Sentence"},{"id":"T67","span":{"begin":715,"end":988},"obj":"Sentence"},{"id":"T68","span":{"begin":989,"end":998},"obj":"Sentence"},{"id":"T69","span":{"begin":999,"end":1117},"obj":"Sentence"},{"id":"T70","span":{"begin":1118,"end":1749},"obj":"Sentence"},{"id":"T71","span":{"begin":1750,"end":2100},"obj":"Sentence"},{"id":"T72","span":{"begin":2101,"end":2386},"obj":"Sentence"},{"id":"T73","span":{"begin":2387,"end":2585},"obj":"Sentence"},{"id":"T74","span":{"begin":2586,"end":2726},"obj":"Sentence"},{"id":"T75","span":{"begin":2727,"end":2834},"obj":"Sentence"},{"id":"T76","span":{"begin":2835,"end":2986},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

LitCovid-PD-HP

{"project":"LitCovid-PD-HP","denotations":[{"id":"T8","span":{"begin":2076,"end":2081},"obj":"Phenotype"}],"attributes":[{"id":"A8","pred":"hp_id","subj":"T8","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

2_test

{"project":"2_test","denotations":[{"id":"32496926-24121034-132195666","span":{"begin":137,"end":139},"obj":"24121034"},{"id":"32496926-24121034-132195667","span":{"begin":321,"end":323},"obj":"24121034"},{"id":"32496926-16115318-132195668","span":{"begin":710,"end":712},"obj":"16115318"},{"id":"32496926-18279660-132195669","span":{"begin":2357,"end":2359},"obj":"18279660"},{"id":"32496926-16115318-132195670","span":{"begin":2376,"end":2378},"obj":"16115318"},{"id":"32496926-31160783-132195671","span":{"begin":2379,"end":2381},"obj":"31160783"},{"id":"32496926-23873408-132195672","span":{"begin":2382,"end":2384},"obj":"23873408"},{"id":"32496926-32221306-132195673","span":{"begin":2578,"end":2580},"obj":"32221306"},{"id":"32496926-15078100-132195674","span":{"begin":2827,"end":2829},"obj":"15078100"},{"id":"32496926-9068613-132195675","span":{"begin":2830,"end":2832},"obj":"9068613"}],"text":"4.1.1. Hindrance of receptor recognition process\nThe S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19]. The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19]. The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13]. Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).\nFigure 1. Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response. CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.\nACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.\nIn addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23]. A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25]. CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25]. CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27]. Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1)."}

PMC:7441788 / 7499-10485 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7441788 / 7499-10485 JSON TXT