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The Mechanism of Glycosylation in SARS-CoV-2 Infection and Application in Drug Development

Wenjie Liu , Kaihui Liu , Yanwei Zhang , Liang Wang , Mengyi Zhang , Jing Li

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (4) : 524 -532.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (4) : 524-532 DOI: 10.7536/PC200647
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The Mechanism of Glycosylation in SARS-CoV-2 Infection and Application in Drug Development
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Abstract

Coronavirus(CoV) is a class of enveloped, positive-sense single-stranded RNA viruses which can infect humans and animals. At the end of 2019, a novel β-coronavirus SARS-CoV-2(Severe acute respiratory syndrome-coronavirus-2) has started to spread from person to person, and the virus-related disease "COVID-19"(Coronavirus disease 2019) poses a serious threat to global public health in different countries. Glycosylation is a post-translational modification that exists on proteins, which can affect the protein folding, stability, and the binding between virus and host receptors. Spike(S) protein determines the tropism of the virus to the host. A plenty of studies have shown that the spike(S) protein in the SARS-CoV-2 envelope and the main receptor on the host cell, Angiotensin converting enzyme 2(ACE2), are highly glycosylated proteins. To explore the role of glycosylation in virus infection and host immune response, this review summarizes the infection mechanism of SARS-CoV-2, the glycosylation modifications of recombinant S protein and host receptor protein ACE2, and the effects of glycosylation on the interaction between virus and host cells. Finally, based on the mechanism of glycosylation, we propose novel potential strategies for COVID-19 diagnosis and anti-virus drug development, which provides new directions for the diagnosis and treatment of COVID-19.

Contents

1 Introduction

2 The infection mechanism of SARS-CoV-2

3 S protein: highly glycosylated viral tropic protein

3.1 Viral glycosylation mechanism: host-dependent glycosylation modification system

3.2 Subtypes of glycosylation and the related sites

3.3 The role of viral protein glycosylation

4 Glycosylation modification of host receptor protein ACE2

5 SARS-CoV-2 detection and drug intervention strategies based on glycosylation

5.1 Development of efficient and sensitive kits using agglutination

5.2 Drugs that affects glycosylation

6 Conclusion and outlook

Graphical abstract

Keywords

novel coronavirus / glycosylation / Spike protein / diagnosis / anti-virus drug

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Wenjie Liu, Kaihui Liu, Yanwei Zhang, Liang Wang, Mengyi Zhang, Jing Li. The Mechanism of Glycosylation in SARS-CoV-2 Infection and Application in Drug Development. Progress in Chemistry, 2021, 33(4): 524-532 DOI:10.7536/PC200647

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1 Introduction

Coronavirus (CoV) is an important pathogen that can infect vertebrates such as humans. It is one of the largest RNA viruses ever identified in terms of genome size and genetic complexity (genome about 25-32 kb; The diameter of virion was 118 ~ 140 nm[1]. CoV can infect the respiratory tract, gastrointestinal tract, liver and central nervous system of humans, livestock, mice and a variety of wild animals (such as birds and bats), and cause varying degrees of symptoms of infection. The subfamily Coronaviridae includes four genera: alpha-coronavirus, beta-coronavirus, gamma-coronaviruses, and delta-coronaviridae (Figure 1). Among them, α-coronavirus and β-coronavirus mostly infect mammals, and γ-coronalvirus and δ-coronalvirus mostly infect birds and fish. Before 2019, six coronaviruses were found to cause human disease, four of which (229E, OC43, NL63 and HKU1) mainly infected the upper respiratory tract and gastrointestinal tract, usually causing only common cold symptoms in immunocompetent individuals[2][3]. However, Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle east respiratory syndrome coronavirus (MERS-CoV) can infect the lower respiratory tract and cause Severe respiratory disease.
At the end of 2019, the seventh beta-coronavirus that can cause human diseases was discovered. The International Committee on Taxonomy of Viruses named SARS-CoV-2 (Severe acute respiratory syndrome-coronavirus-2) according to its characteristics. In early studies, the virus was also called 2019-nCoV. The disease caused by SARS-CoV-2 is known as COVID-19 (Coronavirus disease 2019). Sequence analysis showed that SARS-CoV-2 shared 96.2% sequence identity with a coronavirus found in horseshoe bats (GISAID accession number EPI _ ISL _ 402127-402130), but only 80.3% identity with SARS, confirming the zoonotic origin of SARS-CoV-2. However, the animal host of the virus has not yet been identified[4]. The severity of SARS-CoV-2 infection in humans varies from asymptomatic to mild (only mild fever and fatigue, no pneumonia) and a small number of severe (dyspnea and/or hypoxemia), with more severe complications such as acute respiratory distress syndrome (ARDS) and other organ failure. Recent studies have found that SARS-CoV-2 not only infects the alveoli and causes alveolar collapse and ARDS, but also infects the heart, brain and nervous system, kidney, intestinal tract and other parts of the human body, causing serious damage to the heart, brain and other organs by inducing excessive immune response[5][6][7][8]. In addition, the virus can also affect the coagulation function of patients and cause thrombosis[9]. At present, COVID-19 has caused hundreds of millions of confirmed cases and millions of deaths worldwide. A thorough and comprehensive understanding of SARS-CoV-2 is of great significance for the diagnosis and drug research and development of COVID-19.
SARS-CoV-2 is an enveloped positive-strand RNA virus. The Nucleocapsid composed of the genome RNA and phosphorylated Nucleocapsid protein (N) is embedded in a phospholipid layer containing Envelope protein (E), Membrane protein (M) and Spike protein (S) (Fig. 2). S protein exists in the form of trimer and is arranged alternately with E protein and M protein, all of which are highly glycosylated[10]. The E and M proteins are mainly involved in the assembly of the virus, the N protein encapsulates the genome to form a nucleoprotein complex, and the S protein mediates the invasion of the virus mainly by binding to host cell receptors.

2 Infection mechanism of novel coronavirus

The invasion mechanism of SARS-Cov-2 is complex. On the one hand, the virus S protein binds to the host Angiotensin-converting enzyme 2 (ACE2) to enter the host cell. On the other hand, the host Transmembrane serine protease 2 (Transm embrane protease serine 2, TMPRSS2) and endosomal cathepsin B and L (Cysteine proteases cathepsin B and L, Cat B/L) cooperate to trigger the S protein[11][12].
S protein is divided into two functional subunits: the S1 and the S2. The S1 is responsible for binding to ACE2 and causing conformational changes of S protein, and the S2 is responsible for fusion with the host cell membrane. Hoffmann et al. Used the replication-defective Vesicular stomatitis virus (VSV) model containing SARS-CoV-2 S protein to study the mechanism of SARS-CoV-2 entering cells, and found that SARS-CoV-2 was easy to infect SARS-sensitive cell lines, which showed that the two viruses had similarities in receptor selection[13]. Analysis of the Receptor binding domain (RBD) of the S protein of SARS-CoV-2 revealed that most of the amino acids essential for binding to ACE2 are conserved in SARS-CoV. Expression of ACE2 in SARS-CoV-2 and SARS- insensitive BHK-21 cells resulted in infection of Receptor binding domain cells, whereas transfection with the Receptor for MERS-CoV, Dipeptidyl peptidase 4 (DPP4) or HCoV-229E[14]. This study shows that SARS-CoV-2, like SARS, uses ACE2 as a receptor to invade host cells[13]. The results of this study are the same as those found by Zhang Yongzhen and Shi Zhengli[15][16]. In February 2020, McLellan et al. Of the University of Texas at Austin reported the first cryo-electron microscopic structure of SARS-CoV-2 S protein, and found that the binding capacity of SARS-CoV-2 S protein to ACE2 was 10-20 times stronger than that of SAR-CoV. However, after testing three known monoclonal antibodies (S230, m396 and 80R) specific for SAR-CoV RBD,The three antibodies were found to have no significant binding to the S protein of SARS-CoV-2, indicating that the cross-reactivity of the antibodies between the RBDs of the two viruses is limited, which may be due to the unique residues L455, F486, Q493, S494, N501 and Y505 of the S protein of SARS-CoV-2 (five of these six residues are mutated in SARS-CoV as compared to SAR-CoV)[17]. The two rigid proline residues of SARS-CoV S are replaced by flexible glycine residues in SARS-CoV-2 S to form a flexible loop. Molecular modeling showed that the RBD of SARS-CoV-2 S binds more strongly to ACE2, and the unique phenylalanine (F486) in its flexible loop can penetrate into the hydrophobic pocket of ACE2. Because ACE2 is conserved and widely expressed in fish, amphibians, reptiles, birds and mammals, ACE2 in these animals may bind to the RBD of SARS-CoV-2 and become the natural host of SARS-CoV-2. In addition, ACE2 is expressed in almost all tissues or organs such as intestinal tract, testis, kidney and so on. SARS-CoV-2 can be transmitted not only through respiratory droplets, but also through fecal-oral and other routes[18].
After the envelope of SARS-CoV is recognized by ACE2, it must undergo membrane fusion to invade the host cell, while the S protein needs to be cleaved by the host protease before fusion with the membrane. In 2016, Walls et al. Found that in the pre-fusion conformation of SARS-CoV, the S1 and the S2 subunit can be cleaved, and there are important sites on the S2 that can be further cleaved by host proteases. The invasion of SARS-CoV depends on the priming of S protein by TMPRSS2 and Cat B/L[19][20,21]. In order to explore the role of these two proteases in SARS-CoV-2 invasion, Hoffmann et al. Used 293 T cell line (TMPRSS2-,overexpress ACE2) which does not express TMPRSS2 and colon cancer cell line Caco-2 (TMPRSS2+,ACE2) which expresses TMPRSS2 to treat with ammonium chloride (to increase the pH value of the endosome, thereby inhibiting the activity of Cat B/L), and found that ammonium chloride could significantly inhibit SARS-CoV S and SARS-CoV-2 S protein-mediated invasion into TMPRSS2-293T cells. But has little effect on the invasion of TMPRSS2+Caco-2 cells. Carmostat mesylate, an inhibitor of TMPRSS2, and compound E64d, an inhibitor of Cat B/L, were further tested. Carmostat mesylate effectively prevented SARS-CoV-2 S from entering TMPRSS2+Caco-2 cells but not TMPRSS2-293T cells, whereas E64d had the opposite effect. This study shows that both CatB/L and TMPRSS2 proteases can assist SARS-CoV and SARS-CoV-2 to invade cells[13].
SARS-CoV-2 and SARS-CoV also have differences in the way they invade cells. The difference is that SARS-CoV-2 S has a unique Furin proteolytic site (RRAR) at the boundary between S1/S2 subunits, and arginine (R) plays a key role in viral fusion/entry and protein maturation, which enhances cell-cell fusion but does not affect viral entry into cells. Therefore, compared with SARS-CoV, the presence of the furin cleavage site enlarges the range of infection of SARS-CoV-2 on mammalian cells and tissues such as humans, increases its transmissibility and/or changes its pathogenicity[22].

3 S Protein: Highly Glycosylated Virus-tropic Protein

Glycosylation is one of the most extensive, complex and important post-translational modifications of proteins in life, which mainly includes N-linkage, O-linkage, C-linkage and glycosylphosphatidylinositol-anchored linkage.These glycosylation modifications can affect the spatial conformation, stability, activity and localization of proteins, and play a key role in biological processes such as molecular recognition, signal transduction and immune response[23]. S protein is the only antigen on the surface of coronavirus, which has a high degree of glycosylation and is a class I viral fusion protein. The study of S protein and its surface glycosylation modification is of great significance for virus detection, vaccine development and drug targeting.

3.1 Mechanisms of viral glycosylation:a host-dependent glycosylation modification system

Viruses have a simple structure and lack glycosylation modification enzymes.There are two main types of glycosylation of viral proteins identified so far:N-glycan and O-glycan.the addition of these glycosylations is mainly dependent on the glycosylation modification system of the host cell(Figure 3)[24,25]。
N-glycan:a sugar chain is linked to a protein by a—NH2at the end of an asparagine(Asn,N)residue in the protein sequence Asn-Xaa-Ser/Thr or Asn-Xaa-Cys(Xaa is any amino acid except Pro).According to the fine structure of the end,N-glycan can be divided into high mannose type,complex type and hybrid type.The processing of N-glycan begins in the endoplasmic reticulum and matures in the Golgi apparatus.The assembly of 14 oligosaccharide(GlcNAc2Man9Glc3)precursors Lin to dolichol-phospholipids(Dol-P)in that endoplasmic reticulum membrane(ER)is initiated,and then the Dol-P-linked oligosaccharides are transfer to the Asn-terminal—NH2of the protein by Oligosaccharyl transferase(OST),Sugar chains continue to be processed in the endoplasmic reticulum(ER)by a series of glycosyl-modifying enzymes,and then Man8GlcNAc2glycosylated proteins are transported to the Golgi apparatus,where they continue to be processed by glycosyl-modifying enzymes:different monosaccharide molecules are removed or added,eventually forming structurally diverse glycoforms 。
O-glycan:the glycosylation of a sugar chain to a protein by the terminal—OH of a serine(Ser)or threonine(Thr)residue of the protein occurs in the cytoplasm,starting with the GalNAc-T catalyzed Ser/Thr-GalNAc,Subsequently,eight different"Core glycoforms"are produced under the catalysis of different glycosyltransferases,of which Core 1-4 are more common,and these Core glycoforms are further processed by glycosyltransferases to produce complex and diverse glycoforms。

3.2 Type and position of glycosylation

the S protein is a key protein for viral infection of cells,responsible for binding to host cell receptors and membrane fusion.Generally,S has two types of glycosylation:N-glycosylation and O-glycosylation.the N-glycan modification of 23 potential asparagines in the S protein of SARS-CoV has been found in the early stage,and the glycosylation of 13 N-sites(118,119,227,269,318,330,357,783,1056,1080,1140,1155 and 1176)has been confirmed by mass spectrometry and proteomics.in addition,7 N-glycan sites(109,118,119,158,227,58)in the S protein of SARS-CoV have been identified by site-directed mutagenesisDendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin(DC-SIGN)and Liver/lymph node-specific intercellular adhesion molecule-3-grabbing nonintegrin(L-SIGN)are the key structures that mediate viral entry into the host[26,27][28]。
Wrapp et al.Constructed a large portion of the extracellular domain of the SARS-CoV-2 S protein,including 44 glycosylation sites of 66 N-glycans per S protein trimer[17]。 in May 2020,Crispin et al.of The University of Southampton in the United Kingdom used site-specific mass spectrometry to identify 22 N-glycosylation sites on recombinant SARS-CoV-2 S protein in 293 F cells,of which 18 glycosylation sites were conserved in SARS-CoV S protein(Figure 4),and found that N-glycan included three types:high mannose type,hybrid type and complex type(Figure 3),of which the complex type had a higher content of sugar chains;the types and abundances of polysaccharides at different glycosylation sites were quite different.N234 and N709 were mainly high mannose type.N61,N122,N603,N717,N801 and N1074 have both high mannose and complex forms[29]。 At the same time,Yang Hao of West China Hospital of Sichuan University used the same treatment method to analyze the N-glycoprotein of S protein expressed by insect cells and 293 cells,and found that the S protein expressed by insect cells was mostly high mannose type,containing 38 kinds of N-sugar chain configurations,while the sugar chain expressed by 293 cells was mainly complex sugar chain,containing 157 kinds of N-sugar chain configurations[30]。 University of Georgia Azadi et al.expressed the subunit(Val16-Gln690)and S2subunit(Met697-Pro1213)of SARS-CoV-2 S protein in 293 T cells,and identified 17 glycosylation modifications of S protein by mass spectrometry analysis after enzymatic hydrolysis,and the sugar chain types were mainly high mannose type and complex type,of which N234 and N282 were located in the RBD of the S1,and their sugar chain terminals contained more sialic acid,which was speculated to be involved in the binding with ACE2[31]; Similar to the results reported by Crispin et al.,this study also found that the sugar chains of Man5GlcNAc2existed at more glycosylation sites,while no glycosylation modification was found at five potential N-glycosylation sites(N17,N603,N1134,N1158,N1173 )。
in addition,a proline(Pro,P)was inserted In front of the furin protease site of SARS-CoV-2 S protein to form PRRAR,P,which can make the main chain atoms of the protein be cyclized into a ring structure.the formation of PRRAR,P leads to O-glycan modification at the nearby Ser673,Thr678 and Ser686 sites.Although the function of these sugar chains is uncertain,it may form a"Mucin-like domain"to shield the epitope or key amino acids of S protein[32]。 Azadi et al.Also identified two new O-glycosylation sites(T323/S325)in the RBD region of the S1subunit.The O-glycan of Core 1 type(HexNAc,HexNAcHex and HexNAcHexNeuAc2)is dominant in T323,while the O-glycan modification of HexNAcHe xNeuAc occurs only in S325 when the sugar chain structure of T323 is HexNAcHe xNeuAc[31]。
the above results indicate that the glycosylation levels and sugar chain types of S protein obtained from different expression systems(HEK293 and insect cells),even from different studies of the same cell(HEK293),are different,indicating that the glycosylation modifications of S protein are diverse and heterogeneous,which may lead to different binding activities with ACE2.Therefore,a thorough understanding of the glycosylation of S protein,especially in the RBD region,is crucial for understanding the invasion of SARS-CoV-2 and preparing effective vaccine antigens。

3.3 Role of viral protein glycosylation

Glycosylation of viral proteins plays a key role in protein folding,receptor recognition,infectivity,and immune evasion[25]。 Mutations In some glycosylation sites can lead to protein folding failure and affect the final assembly and maturation of the virus.There are also some sugar chains involved in the recognition of lectin receptors on the surface of host cells,which affect the invasion of viruses to hosts.in addition,some sugar chains will cover the epitopes of proteins,thus achieving the purpose of evading host immune surveillance。
Viruses have evolved a variety of immune evasion strategies,in which the glycan on the surface of coronavirus S protein masks some epitopes,limits the ability of the host to acquire neutralizing antibodies and hinders the humoral immune response,which is conducive to virus escape.Walls et al.Showed that HCoV-NL63S was covered by an extensive glycan layer containing 102 N-linked oligosaccharides that masked its epitopes and shielded antibody binding[33]。 Watanabe et al.Also observed glycan shielding of the sugar chains(N165,N234,N343)proximal to the RBD of SARS-CoV-2 S,especially when the RBD is in a"down"state unbound to the receptor[29]。
C-type lectins(such as DC/L-SIGN)on the surface of host cells can initiate immune response by recognizing sugar chains of viral proteins.the glycans on the S protein of SARS-CoV are mainly high mannose and heterozygous.After the glycans were removed by Endoglycosidase H(Endo H),the infectivity of the virus decreased sharply in a time-dependent manner in cells expressing DC/L-SIGN,and also decreased in cells expressing ACE2,suggesting that the glycans not only bind to DC/L-SIGN,but also may maintain the conformation of S protein when it binds to ACE2[34]。 Certain glycans at specific sites are essential for L-SIGN-mediated infection,and single mutations at these sites(N109Q,N118Q,N119Q and N227Q)will result in a severe decrease in the ability of the virus to bind L-SIGN,and the infectivity of the mutant virus will also be reduced to 30%-40%of the original.This study shows that sugar chains play an important role in SARS-CoV invasion mediated by DC/L-SIGN,but the deglycosylation of specific sites only leads to the decrease of infectivity,not the complete loss of infection,indicating that there is a synergistic effect between sugar chains to maintain viral invasion[27]。 It has also been reported that Mannose-binding lectin(MBL)and DC-SIGN may recognize some of the same glycans on SARS-CoV S.Therefore,MBL can block the effective binding of SARS-CoV S to DC-SIGN on recipient cells and interfere with the invasion of the virus[35]。 in addition,some viral glycoproteins can also specifically recognize certain glycans on the surface of host cells,thus affecting viral invasion,infection and tropism.For example,Li et al found that In addition to DPP4,MERS-CoV also binds to sialic acid(Sia)at the end of host cell glycan,which may affect its host range and tissue tropism[36]。

4 Glycosylation Modification of Host Receptor Protein ACE2

ACE2 is an exopeptidase (EC 3.4.15.1) that catalyzes the conversion of angiotensin I to angiotensin II and is distributed on cells in the heart, kidney, testis, gastrointestinal tract, brain, and lungs of humans and animals. It is a homolog of angiotensin-converting enzyme (ACE), but has the opposite physiological function. They antagonize each other and jointly maintain the balance of Renin-angiotensin system (RAS), stabilize blood pressure and the internal environment of water and electrolyte, and regulate cardiovascular function. If ACE2 is relatively deficient and angiotensin is dominant, it will lead to increased vasoconstriction and hypertension[37].
ACE2 contains two domains: the N-terminal Peptidase domain (PD) and the C-terminal Collectrin-like domain. Recently, Zhou Qiang of West Lake University analyzed the structure of the first ACE2-B0AT1 (an amino acid transporter in the intestine) complex, in which 5 to 7 glycosylation sites of ACE2 were found in the extracellular PD region, which is the region where ACE2 binds to S protein, so the glycosylation of ACE2 may affect the invasion of SARS-CoV-2[38]. A recent study by Shajahan et al. reported N-glycan and O-glycan characterization of hACE2[39]. This study identified glycosylation at all (7) potential N-glycosylation sites (N53, N90, N103, N322, N432, N546 and N690) on hACE2, with the complex glycan being more abundant than the high-mannose and heterozygous glycans, and three new O-glycosylation sites (Ser155, Thr496 and Thr730). Another molecular simulation study showed that the glycosylation of N90 and N322 significantly affected the binding of ACE2 to SARS-CoV-2 S. The authors suggested that the glycosylation of N322 might enhance the binding of ACE2 to SARS-CoV-2, while the glycans of N90 competed with those of N322, and the glycans at this site covered part of the binding interface of RBD of viral S protein, which was not conducive to viral binding[40]. Considering both of them, the existence of sugar chains is conducive to the binding of viruses.
ACE2, as the receptor of SARS-CoV-2 S protein, plays an important role in the process of virus invasion. However, if the expression or activity of ACE2 is interfered, it will affect the balance of RAS, lead to hypertension or excessive activation of AT1 receptors in the lung, increase the permeability of pulmonary capillaries, and lead to acute lung injury and other organ injuries. Therefore, it is a feasible antiviral strategy to inhibit the ability of virus to bind ACE2 without inhibiting the expression or activity of ACE2 by interfering with ACE2 sugar chain.

5 Novel coronavirus detection and drug intervention strategies based on glycosylation

5.1 Development of a highly efficient and sensitive kit using agglutination reaction

agglutination is a serological reaction,that is,granular Antigens(pathogenic microorganisms,proteins,polysaccharides and other small molecules)combine with the corresponding antibodies,in the presence of electrolytes,after a certain period of time,visible agglutination clumps appear.antigens involved in agglutination reactions are called agglutinogens,and antibodies are called agglutinins.the diagnosis of ABO blood group is based on this method,in which the antibody and the sugar antigen on the surface of red blood cells react with each other in a liquid medium.Because of its simple operation and easy reading of the results,it is suitable for large-scale population screening[41]。 We can also screen and obtain the lectin specific to the sugar chain of SARS-CoV-2 on the basis of identifying the composition of SARS-CoV-2 S proteoglycan by mass spectrometry,and then use the lectin to detect SARS-CoV in serum。

5.2 Drugs that interfere with glycosylation

Glycosylated proteins play an important role in both the life course of the virus and the host immune response.Previous studies have shown that the addition or deletion of glycosylation sites on the surface of viral proteins can change the biological characteristics,pathogenicity and antigenicity of viruses.the main component of Tamiflu is oseltamivir phosphate,which can inhibit the activity of neuraminidase on the surface of the virus,and neuraminidase can hydrolyze the sialic acid residues at the end of the hemagglutinin sugar chain of host cells and virions,thus facilitating the separation and diffusion of newly formed virions from infected cells[42]。
Treatment of the cells with an inhibitor of endoplasmic reticulum glucosidase,iminosugar,altered the N-glycan structure of ACE2,decreased the ability of the virus to fuse with the host membrane(without affecting the expression of ACE2 and its ability to bind to S protein),and blocked the invasion of HCoV-NL63[43]。 At the end of March 2020,the US Food and Drug Administration(FDA)issued a limited emergency authorization for the use of two antimalarial drugs(chloroquine and hydroxychloroquine)for the treatment of COVID-19.Zhong Nanshan and others in China also found that the SARS-CoV-2 virus was suppressed significantly faster in patients using chloroquine than in patients not using it[44]。 in the study of SARS-CoV in 2005,Vincent et al.found that chloroquine could interfere with the terminal glycosylation of ACE2,resulting in a decrease in the binding affinity between ACE2 and SARS-CoV S protein.in view of the fact that both SARS-CoV-2 and SAR-CoV use ACE2 as their receptor,it is inferred that chloroquine is one of the effective drugs against SARS-CoV-2.However,in clinical trials,chloroquine has been Found to have strong cardiotoxic side effects,and the detailed mechanism[45]。 glycosylation of S protein also plays a key role in SARS-CoV-2 invasion,so inhibition of glycosylation formation is expected to play an antiviral role from both ACE2 and S protein.Our group has developed a series of glycosidase inhibitors in the early stage,and these glycosidase inhibitors may also play an antiviral role by affecting the glycosylation process of the host and virus,and related testing work is currently under way[46,47]。

6 Conclusion and prospect

SARS-CoV-2 is a newly discovered coronavirus that can infect humans.The invasion of SARS-CoV-2 depends on the S protein in the envelope and ACE2 on the surface of host cells, and the glycosylation of these two proteins plays an important role in virus invasion, receptor binding, glycan shielding and immune response.
However, current glycosylation analysis of S and ACE2 proteins is mostly based on recombinant proteins obtained from mammalian cells or insect cell expression systems, and the glycosylation of these recombinant proteins in vitro may be different from that of viral S protein and host ACE2 protein in COVID-19 patients. Pharmaceutical intervention based on the development of sugar structure of recombinant proteins may differ between different COVID-19 patients. Therefore, glycosylation analysis of virus samples and tissue samples from COVID-19 patients is urgently needed in order to more accurately and truly analyze the mechanism of glycosylation in novel coronavirus infection and host immune response, which is conducive to the development of more sensitive SARS-CoV-2 detection methods and more specific vaccines, antibodies and antiviral drugs.

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Funding

the Open Fund of Beijing Molecular Science National Research Center(BNLMS201826)

the Basic Research Funds for Central Universities(63201105)

and National Natural Science Foundation of China(82073879)

and National Natural Science Foundation of China(81573282)

and National Natural Science Foundation of China(U1801288)

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