LitCovid-sentences  

PMC:7048180 / 1661-10991 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T14 0-128 Sentence denotes Very recently, a novel coronavirus which was temporarily named “2019 novel coronavirus (2019-nCoV)” emerged in Wuhan, China [1].
T15 129-406 Sentence denotes As of 1 February 2020, 2019-nCoV has resulted in a total of 11,821 laboratory-confirmed human infections in China, including 259 deaths, and 132 exported cases in 23 countries outside of China (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports).
T16 407-499 Sentence denotes Currently, there is no vaccine or effective antiviral treatment against 2019-nCoV infection.
T17 500-556 Sentence denotes Based on the phylogenetic analysis (GISAID accession no.
T18 557-816 Sentence denotes EPI_ISL_402124) [2], 2019-nCoV belongs to lineage B betacoronavirus and shares high sequence identity with that of bat or human severe acute respiratory syndrome coronavirus-related coronavirus (SARSr-CoV) and bat SARS-like coronavirus (SL-CoV) (Figure 1(a)).
T19 817-942 Sentence denotes In previous studies, a number of potent monoclonal antibodies against SARS coronavirus (SARS-CoV) have been identified [3–7].
T20 943-1208 Sentence denotes These antibodies target the spike protein (S) of SARS-CoV and SL-CoVs, which is a type I transmembrane glycoprotein and mediates the entrance to human respiratory epithelial cells by interacting with cell surface receptor angiotensin-converting enzyme 2 (ACE2) [8].
T21 1209-1372 Sentence denotes More specifically, the 193 amino acid length (N318-V510) receptor binding domain (RBD) within the S protein is the critical target for neutralizing antibodies [9].
T22 1373-1591 Sentence denotes Some of the antibodies recognize different epitopes on RBD; e.g. the SARS-CoV neutralizing antibodies CR3014 and CR3022 bound noncompetitively to the SARS-CoV RBD and neutralized the virus in a synergistic fashion [5].
T23 1592-1841 Sentence denotes We predicted the conformation of 2019-nCoV RBD as well as its complex structures with several neutralizing antibodies, and found that the modelling results support the interactions between 2019-nCoV RBD and certain SARS-CoV antibodies (Figure 1(b)).
T24 1842-1945 Sentence denotes This could be due to the relatively high identity (73%) of RBD in 2019-nCoV and SARS-CoV (Figure 1(c)).
T25 1946-2158 Sentence denotes For instance, residues in RBD of SARS-CoV that make polar interactions with a neutralizing antibody m396 as indicated by the complex crystal structure [10] are invariably conserved in 2019-nCoV RBD (Figure 1(d)).
T26 2159-2251 Sentence denotes In the structure of SARS-CoV-RBD-m396, R395 in RBD formed a salt bridge with D95 of m396-VL.
T27 2252-2390 Sentence denotes Concordantly, the electrostatic interaction was also observed in the model of 2019-nCoV-RBD-m396, forming by R408 (RBD) and D95 (m396-VL).
T28 2391-2507 Sentence denotes This analysis suggests that some SARS-CoV-specific monoclonal antibodies may be effective in neutralizing 2019-nCoV.
T29 2508-2749 Sentence denotes In contrast, the interactions between antibody F26G19 [11] or 80R [12] and the RBD in 2019-nCoV decreased significantly due to the lack of salt bridges formed by R426-D56 in SARS-CoV-RBD-F26G19 or D480-R162 in SARS-CoV-RBD-80R, respectively.
T30 2750-2953 Sentence denotes Furthermore, while most of the 80R-binding residues on the RBD of SARS-CoV are not conserved on RBD of 2019-nCoV (Figure 1(c)), it is unlikely that the antibody 80R could effectively recognize 2019-nCoV.
T31 2954-3204 Sentence denotes Therefore, it is urgent to experimentally determine the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV.
T32 3205-3306 Sentence denotes Figure 1. (a) Phylogenetic analysis of 2019-nCoV spike glycoprotein from its protein BLAST sequences.
T33 3307-4175 Sentence denotes The neighbour-joining tree was constructed using MEGA X, tested by bootstrap method of 2000 replicates, and edited by the online tool of iTOL (v5). (b) The simulated model of 2019-nCoV RBD binding to SARS-CoV-RBD-specific antibodies (m396, 80R, and F26G19). (c) Protein sequence alignment of 2019-nCoV and SARS-CoV RBD, showing the predominant residues that contribute to interactions with ACE2 or SARS-CoV-specific antibodies. (d) The comparison of the complex structures of SARS-CoV-RBD and SARS-CoV-RBD-specific antibodies (shown in the first row) and models of 2019-nCoV-RBD and SARS-CoV-RBD-specific antibodies (shown in the second row). (e) Binding of monoclonal antibodies to 2019-nCoV RBD determined by ELISA. (f) Binding profiles of 2019-nCoV RBD to ACE2 and antibodies, and (g) competition of CR3022 and ACE2 with 2019-nCoV RBD measured by BLI in OctetRED96.
T34 4176-4281 Sentence denotes Binding kinetics was evaluated using a 1:1 Langmuir binding model by ForteBio Data Analysis 7.0 software.
T35 4282-4351 Sentence denotes In this study, we first expressed and purified 2019-nCoV RBD protein.
T36 4352-4460 Sentence denotes We also predicted the conformations of 2019-nCoV RBD and its complex with the putative receptor, human ACE2.
T37 4461-4634 Sentence denotes Comparison of the interaction between the complex of ACE2 [13] and SARS-CoV RBD and homology model of ACE2 and 2019-nCoV RBD revealed similar binding modes (data not shown).
T38 4635-4772 Sentence denotes In both complexes, β5–β6 loop and β6–β7 loop form extensive contact, including at least seven pairs of hydrogen bonds, with the receptor.
T39 4773-4893 Sentence denotes Notably, R426 on the forth α helix in SARS-CoV RBD builds a salt bridge with E329 and a hydrogen bond with Q325 on ACE2.
T40 4894-5108 Sentence denotes However, the arginine (R426 in SARS-CoV RBD) to asparagine (N439) mutation in 2019-nCoV RBD abolished the strong polar interactions, which may induce a decrease in the binding affinity between RBD and the receptor.
T41 5109-5292 Sentence denotes Interestingly, a lysine (K417 in 2019-nCoV RBD) replacement of valine (V404 in SARS-CoV RBD) on β6 formed an extra salt bridge with D30 on ACE2, which may recover the binding ability.
T42 5293-5414 Sentence denotes These data indicate that the RBD in S protein of 2019-nCoV may bind to ACE2 with a similar affinity as SARS-CoV RBD does.
T43 5415-5582 Sentence denotes Indeed, we measured the binding of 2019-nCoV RBD to human ACE2 by the biolayer interferometry binding (BLI) assay, and found that 2019-nCoV RBD bound potently to ACE2.
T44 5583-5755 Sentence denotes The calculated affinity (KD) of 2019-nCoV RBD with human ACE2 was 15.2 nM (Figure 1(f)), which is comparable to that of SARS-CoV spike protein with human ACE2 (15 nM) [14].
T45 5756-5909 Sentence denotes These results indicate that ACE2 could be the potential receptor for the new coronavirus, and that the expressed 2019-nCoV RBD protein is functional [2].
T46 5910-6292 Sentence denotes Next, we expressed and purified several representative SARS-CoV-specific antibodies which have been reported to target RBD and possess potent neutralizing activities, including m396 [3], CR3014 [4], CR3022 [5], as well as a MERS-CoV-specific human monoclonal antibody m336 developed by our laboratory [15], and measured their binding ability to 2019-nCoV RBD by ELISA (Figure 1(e)).
T47 6293-6392 Sentence denotes Surprisingly, we found that most of these antibodies did not show evident binding to 2019-nCoV RBD.
T48 6393-6468 Sentence denotes To confirm this result, we further measured the binding kinetics using BLI.
T49 6469-6533 Sentence denotes An irrelevant anti-CD40 antibody was used as a negative control.
T50 6534-6695 Sentence denotes Similarly, the antibody m396, which was predicted to bind 2019-nCoV RBD (Figure 1(d)), only showed slight binding at the highest measured concentration (2.0 µM).
T51 6696-6845 Sentence denotes Further studies are needed to solve the high-resolution structure of 2019-nCoV RBD and understand why it could not be recognized by these antibodies.
T52 6846-6988 Sentence denotes Notably, one SARS-CoV-specific antibody, CR3022, was found to bind potently with 2019-nCoV RBD as determined by ELISA and BLI (Figure 1(e,f)).
T53 6989-7135 Sentence denotes It followed a fast-on (kon of 1.84 × 105 Ms−1) and slow-off (koff of 1.16 × 10−3 s−1) binding kinetics, resulting in a KD of 6.3 nM (Figure 1(f)).
T54 7136-7291 Sentence denotes This antibody was isolated from blood of a convalescent SARS patient and did not compete with the antibody CR3014 for binding to recombinant S protein [5].
T55 7292-7431 Sentence denotes To further elucidate the binding epitopes of CR3022, we measured the competition of CR3022 and human ACE2 for the binding to 2019-nCoV RBD.
T56 7432-7617 Sentence denotes The streptavidin biosensors labelled with biotinylated 2019-nCoV RBD were saturated with human ACE2 in solution, followed by the addition of the test antibodies in the presence of ACE2.
T57 7618-7735 Sentence denotes As shown in Figure 1(g), the antibody CR3022 did not show any competition with ACE2 for the binding to 2019-nCoV RBD.
T58 7736-7908 Sentence denotes These results suggest that CR3022, distinct from the other two SARS-CoV antibodies, recognizes an epitope that does not overlap with the ACE2 binding site of 2019-nCoV RBD.
T59 7909-8005 Sentence denotes The RBD of 2019-nCoV differs largely from the SARS-CoV at the C-terminus residues (Figure 1(c)).
T60 8006-8207 Sentence denotes Our results implied that such a difference did not result in drastic changes in the capability to engage the ACE2 receptor, but had a critical impact on the cross-reactivity of neutralizing antibodies.
T61 8208-8501 Sentence denotes Some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the receptor binding site of SARS-CoV failed to bind 2019-nCoV spike protein, indicating that it is necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.
T62 8502-8736 Sentence denotes Interestingly, it was reported that the antibody CR3022 completely neutralized both the wild-type SARS-CoV and the CR3014 escape viruses at a concentration of 23.5 μg/ml, and that no escape variants could be generated with CR3022 [5].
T63 8737-8874 Sentence denotes Furthermore, the mixture of CR3022 and CR3014 neutralized SARS-CoV in a synergistic fashion by recognizing different epitopes on RBD [5].
T64 8875-9087 Sentence denotes These results suggest that CR3022 has the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections.
T65 9088-9284 Sentence denotes We expect more cross-reactive antibodies against 2019-nCoV and SARS-CoV or other coronaviruses to be identified soon, facilitating the development of effective antiviral therapeutics and vaccines.
T66 9286-9308 Sentence denotes Supplementary Material
T67 9309-9330 Sentence denotes Supplemental Material