PMC:7441788 / 7473-12955 JSONTXT 25 Projects

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Id Subject Object Predicate Lexical cue
T60 0-4 Sentence denotes 4.1.
T61 6-24 Sentence denotes Antiviral activity
T62 26-32 Sentence denotes 4.1.1.
T63 34-75 Sentence denotes Hindrance of receptor recognition process
T64 76-167 Sentence denotes The S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19].
T65 168-351 Sentence denotes 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].
T66 352-740 Sentence denotes 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].
T67 741-1014 Sentence denotes 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).
T68 1015-1024 Sentence denotes Figure 1.
T69 1025-1143 Sentence denotes Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response.
T70 1144-1775 Sentence denotes 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.
T71 1776-2126 Sentence denotes ACE2, 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.
T72 2127-2412 Sentence denotes In 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].
T73 2413-2611 Sentence denotes 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].
T74 2612-2752 Sentence denotes CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25].
T75 2753-2860 Sentence denotes CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27].
T76 2861-3012 Sentence denotes 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).
T77 3014-3020 Sentence denotes 4.1.2.
T78 3022-3065 Sentence denotes Interference of the membrane fusion process
T79 3066-3193 Sentence denotes CoVs are enveloped RNA viruses, and their cell entry processes involve a principal route of receptor-mediated endocytosis [28].
T80 3194-3358 Sentence denotes Membrane fusion takes place in the endosomal compartment after endocytosis, which needs additional triggers such as pH acidification or proteolytic activation [29].
T81 3359-3598 Sentence denotes Multiple cellular proteases, such as trypsin, furin, proprotein convertase (PC) family, cathepsins, transmembrane protease/serine (TMPRSS) proteases and elastase, are involved in S protein activation, which can induce membrane fusion [30].
T82 3599-3833 Sentence denotes Among them, cathepsin L, with anoptimal pH of 3.0 to 6.5, is most commonly associated with activation of a variety of CoV S proteins [30], such as SARS-CoV [19], MERS-CoV [31], HCoV-229E [32], and mouse hepatitis virus 2 (MHV-2) [33].
T83 3834-3996 Sentence denotes A recent study found that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, in which cathepsin L is critical for priming of SARS-CoV-2 S protein [24].
T84 3997-4346 Sentence denotes A study investigated the detailed mechanism of action of CQ/HCQ in inhibiting SARS-CoV-2 entry, and co-localization of SARS-CoV-2 with early endosomes (EEs) or endolysosomes (ELs) in VeroE6 cells, and the results showed that CQ/HCQ hampered the transport of SARS-CoV-2 from EEs to ELs, indicating that CQ/HCQ might inhibit endosomal maturation [17].
T85 4347-4610 Sentence denotes These studies revealed that the mechanism of anti-CoV activity of CQ/HCQ may involve the inhibition of the endosome acidification process, which might inactivate lysosomal proteases, thus interfering with the fusion of virus and host membranes [34,35] (Figure 1).
T86 4612-4618 Sentence denotes 4.1.3.
T87 4620-4680 Sentence denotes Effects on cell signaling pathway and host defense machinery
T88 4681-4857 Sentence denotes The mitogen-activated protein kinase (MAPK) pathway transmits signals from the cell surface to the nucleus involved in the infection of CoVs such as MHV [36] and SARS-CoV [37].
T89 4858-4997 Sentence denotes CQ could inhibit HCoV-229E replication in human embryonic lung epithelial cells (L132) through suppressing the activation of p38 MAPK [38].
T90 4998-5163 Sentence denotes Moreover, HCQ could markedly induce the production of cellular reactive oxygen species (ROS), which play an important role in the activation of innate immunity [39].
T91 5164-5321 Sentence denotes HCQ also could trigger the host defense mechanism through the mitochondrial antiviral signaling (MAVS) pathway, resulting in anti-dengue virus activity [39].
T92 5322-5482 Sentence denotes Therefore, CQ/HCQ may also exert their antiviral activity by suppressing the activation of p38 MAPK pathway and affecting the host defense machinery (Figure 1).