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Id Subject Object Predicate Lexical cue
T1 0-123 Sentence denotes The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade
T2 125-133 Sentence denotes Abstract
T3 134-218 Sentence denotes In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China.
T4 219-295 Sentence denotes Its genome has been sequenced and the genomic information promptly released.
T5 296-504 Sentence denotes Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs.
T6 505-689 Sentence denotes In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.
T7 691-701 Sentence denotes Highlights
T8 702-809 Sentence denotes • The genomic sequence of 2019-nCoV indicates that the virus clusters with betacoronaviruses of lineage b.
T9 810-935 Sentence denotes • 2019-nCoV S-protein sequence has a specific furin-like cleavage site absent in lineage b CoV including SARS-CoV sequences.
T10 936-1063 Sentence denotes • The furin-like cleavage site in the S-protein of 2019-nCoV may have implications for the viral life cycle and pathogenicity.
T11 1064-1166 Sentence denotes • Campaigns to develop anti-2019-nCoV therapeutics should include the evaluation of furin inhibitors.
T12 1168-1354 Sentence denotes Human coronaviruses (CoV) are enveloped positive-stranded RNA viruses belonging to the order Nidovirales, and are mostly responsible for upper respiratory and digestive tract infections.
T13 1355-1598 Sentence denotes Among them SARS-CoV and MERS-CoV that spread in 2002 and 2013 respectively, have been associated with severe human illnesses, such as severe pneumonia and bronchiolitis, and even meningitis in more vulnerable populations (de Wit et al., 2016).
T14 1599-1811 Sentence denotes In December 2019, a new CoV (2019-nCoV) has been detected in the city of Wuhan, and this emerging viral infection was associated with severe human respiratory disease with a ~2–3% fatality rate (Li et al., 2020).
T15 1812-1942 Sentence denotes The virus that was presumed to have initially been transmitted from an animal reservoir to humans possibly via an amplifying host.
T16 1943-2144 Sentence denotes However human-to-human transmission has been reported, leading to a sustained epidemic spread with >31,000 confirmed human infections, including >640 deaths, reported by the WHO in early February 2020.
T17 2145-2213 Sentence denotes The estimated effective reproductive number (R) value of ~2.90 (95%:
T18 2214-2316 Sentence denotes 2.32–3.63) at the beginning of the outbreak raises the possibility of a pandemics (Zhao et al., 2020).
T19 2317-2403 Sentence denotes This prompted WHO to declare it as a Public Health Emergency of International Concern.
T20 2404-2511 Sentence denotes This is especially relevant because so far there are no specific antiviral treatments available or vaccine.
T21 2512-2711 Sentence denotes Based on its genome sequence, 2019-nCoV belongs to lineage b of Betacoronavirus (Fig. 1 A), which also includes the SARS-CoV and bat CoV ZXC21, the latter and CoV ZC45 being the closest to 2019-nCoV.
T22 2712-2854 Sentence denotes 2019-nCoV shares ~76% amino acid sequence identity in the Spike (S)-protein sequence with SARS-CoV and 80% with CoV ZXC21 (Chan et al., 2020).
T23 2855-3083 Sentence denotes In this article, we focus on a specific furin-like protease recognition pattern present in the vicinity of one of the maturation sites of the S protein (Fig. 1B) that may have significant functional implications for virus entry.
T24 3084-3352 Sentence denotes Fig. 1 Characterization of an nCoV-peculiar sequence at the S1/S2 cleavage site in the S-protein sequence, compared SARS-like CoV. (A) Phylogenetic tree of selected coronaviruses from genera alphacoronavirus (α-Cov) and betacoronavirus (β-CoV), lineages a, b, c and d:
T25 3353-3583 Sentence denotes 2019-nCoV (NC_045512.2), CoV-ZXC21 (MG772934), SARS-CoV (NC_004718.3), SARS-like BM4821 (MG772934), HCoV-OC43 (AY391777), HKU9-1 (EF065513), HCoV-NL63 (KF530114.1), HCoV229E (KF514433.1), MERS-CoV (NC019843.3), HKU1 (NC_006577.2).
T26 3584-3708 Sentence denotes The phylogenetic tree was obtained on the Orf1ab amino acid sequence using the Maximum Likelihood method by Mega X software.
T27 3709-3914 Sentence denotes Red asterisks indicate the presence of a canonical furin-like cleavage motif at site 1; (B) Alignment of the coding and amino acid sequences of the S-protein from CoV-ZXC21 and 2019-nCoV at the S1/S2 site.
T28 3915-3958 Sentence denotes The 2019-nCoV-specific sequence is in bold.
T29 3959-4260 Sentence denotes The sequence of CoV-ZXC21 S-protein at this position is representative of the sequence of the other betacoronaviruses belonging to lineage b, except the one of 2019-nCoV. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
T30 4261-4464 Sentence denotes The proprotein convertases (PCs; genes PCSKs) constitute a family of nine serine secretory proteases that regulate various biological processes in both healthy and disease states (Seidah and Prat, 2012).
T31 4465-4728 Sentence denotes By proteolysis, PCs are responsible for the activation of a wide variety of precursor proteins, such as growth factors, hormones, receptors and adhesion molecules, as well as cell surface glycoproteins of infectious viruses (Seidah and Chretien, 1999) (Table 1 ).
T32 4729-4916 Sentence denotes Seven PCs cleave precursor proteins at specific single or paired basic amino acids (aa) within the motif (R/K)-(2X)n-(R/K)↓, where n = 0, 1, 2, or 3 spacer aa (Seidah and Chretien, 1999).
T33 4917-5060 Sentence denotes Because of their role in the processing of many critical cell surface proteins PCs, especially furin, have been implicated in viral infections.
T34 5061-5239 Sentence denotes They have the potential to cleave specifically viral envelope glycoproteins, thereby enhancing viral fusion with host cell membranes (Izaguirre, 2019; Moulard and Decroly, 2000).
T35 5240-5523 Sentence denotes In the case of human-infecting coronaviruses such as HCoV-OC43 (Le Coupanec et al., 2015), MERS-CoV (Millet and Whittaker, 2014), and HKU1 (Chan et al., 2008) the spike protein has been demonstrated to be cleaved at an S1/S2 cleavage site (Fig. 2 ) generating the S1 and S2 subunits.
T36 5524-5605 Sentence denotes The above three viruses display the canonical (R/K)-(2X)n-(R/K)↓ motif (Table 1).
T37 5606-5763 Sentence denotes Additionally, it has been demonstrated that variation around the viral envelope glycoprotein cleavage site plays a role in cellular tropism and pathogenesis.
T38 5764-5907 Sentence denotes For instance, the pathogenesis of some CoV has been previously related to the presence of a furin-like cleavage site in the S-protein sequence.
T39 5908-6132 Sentence denotes For example, the insertion of a similar cleavage site in the infectious bronchitis virus (IBV) S-protein results in higher pathogenicity, pronounced neural symptoms and neurotropism in infected chickens (Cheng et al., 2019).
T40 6133-6258 Sentence denotes Table 1 Comparative sequences of envelope protein cleavage site(s) in coronaviruses (above) and in other RNA viruses (below).
T41 6259-6301 Sentence denotes Empty boxes: no consensus motif detected..
T42 6302-6413 Sentence denotes Fig. 2 Schematic representation of the human 2019-nCoV S-protein with a focus on the putative maturation sites.
T43 6414-6481 Sentence denotes The domains were previously characterized in SARS-CoV and MERS-CoV:
T44 6482-6672 Sentence denotes Signal peptide (SP), N-terminal domain (NTD), receptor-binding domain (RBD), fusion peptide (FP), internal fusion peptide (IFP), heptad repeat 1/2 (HR1/2), and the transmembrane domain (TM).
T45 6673-6734 Sentence denotes The SP, S1↓S2 and S2′ cleavage sites are indicated by arrows.
T46 6735-7102 Sentence denotes The sequence of different CoV S1/S2 and S2′ cleavage sites were aligned using Multalin webserver (http://multalin.toulouse.inra.fr/multalin/) with manual adjustments and the figure prepared using ESPript 3 (http://espript.ibcp.fr/ESPript/ESPript/) presenting the secondary structure of SARS-CoV S-protein at the bottom of the alignment (PDB 5X58) (Yuan et al., 2017).
T47 7103-7172 Sentence denotes Insertion of furin like cleavage site is surrounded by a black frame.
T48 7173-7399 Sentence denotes Red asterisks indicate the presence of a canonical furin-like cleavage motif at the S1/S2 site. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
T49 7400-7734 Sentence denotes Similarly, in the case of influenza virus, low-pathogenicity forms of influenza virus contain a single basic residue at the cleavage site, which is cleaved by trypsin-like proteases and the tissue distribution of the activating protease(s) typically restricts infections to the respiratory and/or intestinal organs (Sun et al., 2010).
T50 7735-8003 Sentence denotes Conversely, the highly pathogenic forms of influenza have a furin-like cleavage site cleaved by different cellular proteases, including furin, which are expressed in a wide variety of cell types allowing a widening of the cell tropism of the virus (Kido et al., 2012).
T51 8004-8223 Sentence denotes Furthermore the insertion of a multibasic motif RERRRKKR↓GL at the H5N1 hemagglutinin HA cleavage site was likely associated with the hyper-virulence of the virus during the Hong Kong 1997 outbreak (Claas et al., 1998).
T52 8224-8545 Sentence denotes This motif exhibits the critical Arg at P1 and basic residues at P2 and P4, as well as P6 and P8 and an aliphatic Leu at P2’ positions (Table 1) (Schechter and Berger nomenclature (Schechter and Berger, 1968)), typical of a furin-like cleavage specificity (Braun and Sauter, 2019; Izaguirre, 2019; Seidah and Prat, 2012).
T53 8546-8717 Sentence denotes The coronavirus S-protein is the structural protein responsible for the crown-like shape of the CoV viral particles, from which the original name “coronavirus” was coined.
T54 8718-8911 Sentence denotes The ~1200 aa long S-protein belongs to class-I viral fusion proteins and contributes to the cell receptor binding, tissue tropism and pathogenesis (Lu et al., 2015; Millet and Whittaker, 2014).
T55 8912-8970 Sentence denotes It contains several conserved domains and motifs (Fig. 2).
T56 8971-9076 Sentence denotes The trimetric S-protein is processed at the S1/S2 cleavage site by host cell proteases, during infection.
T57 9077-9294 Sentence denotes Following cleavage, also known as priming, the protein is divided into an N-terminal S1-ectodomain that recognises a cognate cell surface receptor and a C-terminal S2-membrane-anchored protein involved in viral entry.
T58 9295-9449 Sentence denotes The SARS-CoV S1-protein contains a conserved Receptor Binding Domain (RBD), which recognises the angiotensin-converting enzyme 2 (ACE2) (Li et al., 2003).
T59 9450-9575 Sentence denotes The SARS-CoV binds to both bat and human cells, and the virus can infect both organisms (Ge et al., 2013; Kuhn et al., 2004).
T60 9576-9660 Sentence denotes The RBD surface of S1/ACE2 implicates 14 aa in the S1 of SARS-CoV (Li et al., 2005).
T61 9661-9823 Sentence denotes Among them, 8 residues are strictly conserved in 2019-nCoV, supporting the hypothesis that ACE2 is also the receptor of the newly emerged nCoV (Wan et al., 2020).
T62 9824-10030 Sentence denotes The S2-protein contains the fusion peptide (FP), a second proteolytic site (S2′), followed by an internal fusion peptide (IFP) and two heptad-repeat domains preceding the transmembrane domain (TM) (Fig. 2).
T63 10031-10155 Sentence denotes Notably, the IFPs of the 2019-nCoV and SARS-CoV are identical, displaying characteristics of viral fusion peptides (Fig. 2).
T64 10156-10428 Sentence denotes While the molecular mechanism involved in cell entry is not yet fully understood, it is likely that both FP and IFP participate in the viral entry process (Lu et al., 2015) and thus the S-protein must likely be cleaved at both S1/S2 and S2′ cleavage sites for virus entry.
T65 10429-10631 Sentence denotes The furin-like S2′ cleavage site at KR↓SF with P1 and P2 basic residues and a P2′ hydrophobic Phe (Seidah and Prat, 2012), downstream of the IFP is identical between the 2019-nCoV and SARS-CoV (Fig. 2).
T66 10632-10823 Sentence denotes In the MERS-CoV and HCoV-OC43 the S1/S2 site is replaced by RXXR↓SA, with P1 and P4 basic residues, and an Ala (not aliphatic) at P2′, suggesting a somewhat less favourable cleavage by furin.
T67 10824-11171 Sentence denotes However, in the other less pathogenic circulating human CoV, the S2′ cleavage site only exhibits a monobasic R↓S sequence (Fig. 2) with no basic residues at either P2 and/or P4 needed to allow furin cleavage, suggesting a less efficient cleavage or higher restriction at the entry step depending on the cognate proteases expressed by target cells.
T68 11172-11371 Sentence denotes Even though processing at S2′ in 2019-nCoV is expected to be a key event for the final activation of the S-protein, the protease(s) involved in this process have not yet been conclusively identified.
T69 11372-11515 Sentence denotes Based on the 2019-nCoV S2′ sequence and the above arguments, we propose that one or more furin-like enzymes would cleave the S2′ site at KR↓SF.
T70 11516-11677 Sentence denotes In contrast to the S2′, the first cleavage between the RBD and the FP (S1/S2 cleavage site, Fig. 2) has been extensively studied for many CoVs (Lu et al., 2015).
T71 11678-11851 Sentence denotes Interestingly the S1/S2 processing site exhibits different motifs among coronaviruses (Fig. 2, site 1 & site 2), with many of them displaying cleavage after a basic residue.
T72 11852-11992 Sentence denotes It is thus likely that the priming process is ensured by different host cell proteases depending on the sequence of the S1/S2 cleavage site.
T73 11993-12138 Sentence denotes Accordingly the MERS-CoV S-protein, which contains a RSVR↓SV motif is cleaved during virus egress, probably by furin (Mille and Whittaker, 2014).
T74 12139-12298 Sentence denotes Conversely the S-protein of SARS-CoV remains largely uncleaved after biosynthesis, possibly due to the lack of a favourable furin-like cleavage site (SLLR-ST).
T75 12299-12601 Sentence denotes In this case, it was reported that following receptor binding the S-protein is cleaved at a conserved sequence AYT↓M (located 10 aa downstream of SLLR-ST) by target cells’ proteases such as elastase, cathepsin L or TMPRSS2 (Bosch et al., 2008; Matsuyama et al., 2010, 2005; Millet and Whittaker, 2015).
T76 12602-12794 Sentence denotes As the priming event is essential for virus entry, the efficacy and extent of this activation step by the proteases of the target cells should regulate cellular tropism and viral pathogenesis.
T77 12795-12960 Sentence denotes In the case of the 2019-nCoV S-protein, the conserved site 2 sequence AYT↓M may still be cleaved, possibly after the preferred furin-cleavage at the site 1 (Fig. 2).
T78 12961-13177 Sentence denotes Since furin is highly expressed in lungs, an enveloped virus that infects the respiratory tract may successfully exploit this convertase to activate its surface glycoprotein (Bassi et al., 2017; Mbikay et al., 1997).
T79 13178-13295 Sentence denotes Before the emergence of the 2019-nCoV, this important feature was not observed in the lineage b of betacoronaviruses.
T80 13296-13548 Sentence denotes However, it is shared by other CoV (HCoV-OC43, MERS-CoV, MHV-A59) harbouring furin-like cleavage sites in their S-protein (Fig. 2; Table 1), which were shown to be processed by furin experimentally (Le Coupanec et al., 2015; Mille and Whittaker, 2014).
T81 13549-13874 Sentence denotes Strikingly, the 2019-nCoV S-protein sequence contains 12 additional nucleotides upstream of the single Arg↓ cleavage site 1 (Fig. 1, Fig. 2) leading to a predictively solvent-exposed PRRAR↓SV sequence, which corresponds to a canonical furin-like cleavage site (Braun and Sauter, 2019; Izaguirre, 2019; Seidah and Prat, 2012).
T82 13875-14150 Sentence denotes This furin-like cleavage site, is supposed to be cleaved during virus egress (Mille and Whittaker, 2014) for S-protein “priming” and may provide a gain-of-function to the 2019-nCoV for efficient spreading in the human population compared to other lineage b betacoronaviruses.
T83 14151-14231 Sentence denotes This possibly illustrates a convergent evolution pathway between unrelated CoVs.
T84 14232-14383 Sentence denotes Interestingly, if this site is not processed, the S-protein is expected to be cleaved at site 2 during virus endocytosis, as observed for the SARS-CoV.
T85 14384-14557 Sentence denotes Obviously much more work is needed to demonstrate experimentally our assertion, but the inhibition of such processing enzyme(s) may represent a potential antiviral strategy.
T86 14558-14772 Sentence denotes Indeed, it was recently shown that in an effort to limit viral infections, host cells that are infected by a number of viruses provoke an interferon response to inhibit the enzymatic activity of furin-like enzymes.
T87 14773-15144 Sentence denotes It was also demonstrated that HIV infection induces the expression of either the protease activated receptor 1 (PAR1) (Kim et al., 2015) or guanylate binding proteins 2 and 5 (GBP2,5) (Braun and Sauter, 2019) that restrict the trafficking of furin to the trans Golgi network (PAR1) or to early Golgi compartments (GBP2,5) where the proprotein convertase remains inactive.
T88 15145-15269 Sentence denotes Altogether, these observations suggest that inhibitors of furin-like enzymes may contribute to inhibiting virus propagation.
T89 15270-15393 Sentence denotes A variety of approaches have been proposed to inhibit furin activity to limit tumour growth, viral and bacterial infection.
T90 15394-15640 Sentence denotes Thus, a variant of the naturally occurring serine protease inhibitor α-1 antitrypsin harbouring a consensus furin cleavage, called α-1 antitrypsin Portland (α1-PDX), inhibits furin and prevents the processing of HIV-1 Env (Anderson et al., 1993).
T91 15641-15942 Sentence denotes The addition of a chloromethylketone (CMK) moiety to the C-terminus of a polybasic cleavage motif and a decanoyl group at the N-terminus to favour cell penetration (dec-RVKR-cmk) irreversibly blocked the enzymatic activity of furin, PC7, PC5, PACE4 and PC7 (Decroly et al., 1996, Garten et al., 1994).
T92 15943-16156 Sentence denotes Finally, the elucidation of the crystal structure of furin resulted in the design of a 2,5-dideoxystreptamine-derived inhibitor, where two molecules of the inhibitor form a complex with furin (Dahms et al., 2017).
T93 16157-16321 Sentence denotes As furin-like enzymes are involved in a multitude of cellular processes, one important issue would be to avoid systemic inhibition that may result in some toxicity.
T94 16322-16625 Sentence denotes Accordingly, it is likely that such small molecule inhibitors, or other more potent orally active ones, possibly delivered by inhalation and exhibiting a slow dissociation rate from furin to allow for sustained inhibition, deserve to be rapidly tested to assess their antiviral effect against 2019-nCoV.
T95 16627-16657 Sentence denotes Appendix A Supplementary data
T96 16658-16736 Sentence denotes The following is the Supplementary data to this article:Multimedia component 1
T97 16738-16753 Sentence denotes Acknowledgments
T98 16754-17061 Sentence denotes This work was supported by a CIHR Foundation grant # 148363 (NGS), a Canada Research Chairs in Precursor Proteolysis (NGS; # 950-231335), and by the European Virus Archive Global (BCo; EVA GLOBAL) funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No 871029.
T99 17062-17180 Sentence denotes Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.antiviral.2020.104742.