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Id Subject Object Predicate Lexical cue
T1 0-111 Sentence denotes Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody
T2 112-142 Sentence denotes Emerging Microbes & Infections
T3 143-145 Sentence denotes X.
T4 146-157 Sentence denotes Tian et al.
T5 159-167 Sentence denotes Abstract
T6 168-176 Sentence denotes ABSTRACT
T7 177-362 Sentence denotes The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 11,900 laboratory-confirmed human infections, including 259 deaths, posing a serious threat to human health.
T8 363-435 Sentence denotes Currently, however, there is no specific antiviral treatment or vaccine.
T9 436-758 Sentence denotes Considering the relatively high identity of receptor-binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess 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.
T10 759-908 Sentence denotes Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM).
T11 909-996 Sentence denotes The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD.
T12 997-1214 Sentence denotes These results suggest that CR3022 may have 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.
T13 1215-1659 Sentence denotes Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g. m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, implying that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.
T14 1661-1789 Sentence denotes Very recently, a novel coronavirus which was temporarily named “2019 novel coronavirus (2019-nCoV)” emerged in Wuhan, China [1].
T15 1790-2067 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 2068-2160 Sentence denotes Currently, there is no vaccine or effective antiviral treatment against 2019-nCoV infection.
T17 2161-2217 Sentence denotes Based on the phylogenetic analysis (GISAID accession no.
T18 2218-2477 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 2478-2603 Sentence denotes In previous studies, a number of potent monoclonal antibodies against SARS coronavirus (SARS-CoV) have been identified [3–7].
T20 2604-2869 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 2870-3033 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 3034-3252 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 3253-3502 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 3503-3606 Sentence denotes This could be due to the relatively high identity (73%) of RBD in 2019-nCoV and SARS-CoV (Figure 1(c)).
T25 3607-3819 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 3820-3912 Sentence denotes In the structure of SARS-CoV-RBD-m396, R395 in RBD formed a salt bridge with D95 of m396-VL.
T27 3913-4051 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 4052-4168 Sentence denotes This analysis suggests that some SARS-CoV-specific monoclonal antibodies may be effective in neutralizing 2019-nCoV.
T29 4169-4410 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 4411-4614 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 4615-4865 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 4866-4967 Sentence denotes Figure 1. (a) Phylogenetic analysis of 2019-nCoV spike glycoprotein from its protein BLAST sequences.
T33 4968-5836 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 5837-5942 Sentence denotes Binding kinetics was evaluated using a 1:1 Langmuir binding model by ForteBio Data Analysis 7.0 software.
T35 5943-6012 Sentence denotes In this study, we first expressed and purified 2019-nCoV RBD protein.
T36 6013-6121 Sentence denotes We also predicted the conformations of 2019-nCoV RBD and its complex with the putative receptor, human ACE2.
T37 6122-6295 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 6296-6433 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 6434-6554 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 6555-6769 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 6770-6953 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 6954-7075 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 7076-7243 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 7244-7416 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 7417-7570 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 7571-7953 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 7954-8053 Sentence denotes Surprisingly, we found that most of these antibodies did not show evident binding to 2019-nCoV RBD.
T48 8054-8129 Sentence denotes To confirm this result, we further measured the binding kinetics using BLI.
T49 8130-8194 Sentence denotes An irrelevant anti-CD40 antibody was used as a negative control.
T50 8195-8356 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 8357-8506 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 8507-8649 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 8650-8796 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 8797-8952 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 8953-9092 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 9093-9278 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 9279-9396 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 9397-9569 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 9570-9666 Sentence denotes The RBD of 2019-nCoV differs largely from the SARS-CoV at the C-terminus residues (Figure 1(c)).
T60 9667-9868 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 9869-10162 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 10163-10397 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 10398-10535 Sentence denotes Furthermore, the mixture of CR3022 and CR3014 neutralized SARS-CoV in a synergistic fashion by recognizing different epitopes on RBD [5].
T64 10536-10748 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 10749-10945 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 10947-10969 Sentence denotes Supplementary Material
T67 10970-10991 Sentence denotes Supplemental Material
T68 10993-11013 Sentence denotes Disclosure statement
T69 11014-11078 Sentence denotes No potential conflict of interest was reported by the author(s).
T70 11080-11085 Sentence denotes ORCID
T71 11086-11134 Sentence denotes Zhengli Shi http://orcid.org/0000-0001-8089-163X
T72 11135-11183 Sentence denotes Shibo Jiang http://orcid.org/0000-0001-8283-7135
T73 11184-11233 Sentence denotes Tianlei Ying http://orcid.org/0000-0002-9597-2843