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). |