Glycopolymers Targeting Viruses: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Ruoyao Mei.

Diseases induced by bacterial and viral infections are common occurrences in our daily life, and the main prevention and treatment strategies are vaccination and taking antibacterial/antiviral drugs. Vaccines can only be used for specific viral infections, and the abuse of antibacterial/antiviral drugs will create multi−drug−resistant bacteria and viruses. Therefore, it is necessary to develop more targeted prevention and treatment methods against bacteria and viruses. Proteins on the surface of bacteria and viruses can specifically bind to sugar, so glycopolymers can be used as potential antibacterial and antiviral drugs.

  • glycopolymer
  • antibacterial
  • antivirus

1. Introduction

In recent decades, a variety of infectious diseases have developed caused by bacteria, including Staphylococcus aureus, Streptococcus haemolyticus type α, Streptococcus haemolyticus type β and viruses including Ebola, Zika, coronavirus (COV) [1]. As a result, different regions are experiencing the spread of diseases caused by these pathogens. With the emergence of superbugs, as well as the global epidemic of COVID−19, wresearchers are facing significant challenges in the prevention and treatment of these diseases due to drug resistance and genetic mutations. At present, the effective prevention and treatment strategy for bacterial diseases is to take antibiotic drugs, and the prevention and treatment strategy for viral diseases is mainly vaccination or taking antiviral drugs. However, vaccines can only be used for specific types of viral infections, and antivirals or antimicrobials can make viruses or bacteria resistant. Therefore, it is important to develop more targeted prevention and treatment methods against highly drug−resistant bacteria and viruses. There are a lot of glycoproteins on the surface of bacteria, viruses and other life forms [2]. Different kinds of sugars can specifically combine with pathogens that contain different types of recognition proteins, such as mannose and Escherichia coli, L−Fucose and Vibrio cholerae, salivary lactose and mumps virus/influenza virus, etc. In addition, the specific binding of sugars and proteins is also affected by a variety of factors, such as the “multivalent effect” of polysaccharides [3[3][4][5][6],4,5,6], topology [7,8,9][7][8][9] (star−shaped, dendritic), heterogeneity [10,11[10][11][12][13][14][15][16],12,13,14,15,16], etc. Therefore, glycopolymers with various structures have been developed to specifically recognize and bind with different bacteria and viruses, so as to achieve the application of inhibiting bacterial infection, virus infection, bacterial detection, etc.

2. Glycopolymers Targeting Viruses

There are a large number of sugars on the surface of cells, which facilitate the transmission of biological information between cells by interacting with specific proteins. In contrast, pathogens also recognize their specific host cells through glycoprotein interactions, that is, glycorecognition proteins (lectins) on the surface of pathogens interact with sugar units on the cell surface to cause viral infection. Based on these interaction mechanisms, the antiviral application of sugar has been heavily studied to develop specific targeting systems that can act as inhibitors of the virus.

2.1. Glycopolymers Targeting Cell Surface Proteins

C−type lectin receptor, dendritic cell−specific intercellular adhesion molecule 3 grabbing nonintegrin (DC−SIGN), is a pattern recognition receptor expressed on macrophages and dendritic cells. It has been identified as a receptor for many pathogens, such as SARS−CoV−2 and HIV. These viruses spread and escape through the binding of DC−SIGN captured by sugar molecules on their surface and dendritic cell−specific ICAM−3 [53][17]. In the context of the recent SARSCoV−2 epidemic, DC−SIGN−mediated viral transmission and innate immune responses have been identified as a potential factor in the pathogenesis of COVID−19 [54][18]. Therefore, the design of glycopolymers with stronger binding capacity to DC−SIGN to inhibit viral binding to DC−SIGN is an attractive strategy to attenuate excessive innate immune responses and prevent disease progression. The ability of glycopolymers binding to DC−SIGN is influenced by multiple factors. Different types and structures of sugars have different degrees of binding capacity to the virus. In addition, wresearchers can also strengthen the binding ability to virus by simulating the glycoproteins. Becer et al. synthesized a mannose−based glycopolymer using copper−mediated living radical polymerization and azide−alkyne [3 + 2] Huisgen cycloaddition reaction to interact with DC−SIGN and inhibit the binding of HIV envelope glycoprotein gp120 to DC−SIGN [55][19]. The binding affinity of the glycocopolymer to DC−SIGN was investigated by multi−channel surface plasmon resonance (MC−SPR). They used a DC−SIGN functionalized surface to evaluate the binding affinity of glycopolymers (Figure 1a), and used gp120 functionalized surfaces for competitive binding studies (Figure 1b). It proved that the increase in mannose content was the key to high affinity; by contrast, the increase in galactose density decreased the affinity for DC−SIGN.
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Figure 1. (a) DC−SIGN−functionalized surfaces were used to evaluate the binding affinity of glycopolymers; (b) gp120−functionalized surfaces are used for competitive binding studies. (Bottom) Schematic diagram of DC−SIGN and gp120 structure and chemical structure of glycopolymer.
Zhang et al. synthesized a series of mannose−based cyclodextrin glycopolymers, including sugar clusters and star sugar copolymers, by CuAAC Huisgen coupling and copper−mediated living radical polymerization [56][20]. These glycoconjugates exhibit high binding affinity to the lectin DC−SIGN, so that these glycopolymers act as an inhibitor to prevent the binding of the HIV envelope protein gp120 to DC−SIGN at nanomolar concentrations. In addition, they also prepared star block glycopolymers and constructed an intelligent drug delivery system with sugar recognition sites, showing application prospects in HIV treatment and intelligent drug delivery (Figure 2).
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Figure 2. Sugar clusters, star type glycopolymers and star block type glycopolymers.
Recently, Cramer et al. designed a mannose−modified poly−L−lysine complex [53][17]. Due to the polyvalent effect of sugar, the complex inhibited the binding of SARS−CoV−2 spike protein to DC−SIGN on the cell surface (Figure 3). As a result, the binding amount of cells pre−incubated with the complex to the virus expressing SARS−CoV−2 spike protein is greatly reduced, which limits the spread of the virus between different cells.
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Figure 3. Interaction of triazole−based mannose analogues with DC−SIGN cells.

2.2. Glycopolymers Targeting Virus Surface Lectin

It is difficult to produce vaccines that are effective against multiple existing and emerging strains of viruses due to virus mutations [57,58,59][21][22][23]. To prevent infection, preventing the virus from attaching to the surface of the cell is the general approach to preventing infection with many viruses, including influenza [60,61,62][24][25][26]. Viruses can adhere to cells by binding to glycans on the cell surface; however, by regulating sugar species, density, topology, etc., glycopolymers can have a stronger virus−binding capacity. Therefore, using glycopolymers to recognize viruses can inhibit viral binding to cells. Viruses can recognize various glycans, such as glycans terminating sialic acids (Neu5Ac), and glycosaminoglycans (GAGs), such as heparan sulfates (HS). However, the use of natural polysaccharides as inhibitors for virus recognition may present many challenges to the safety of clinical applications [63,64][27][28]. Firstly, the molecules are heterogeneous. The preparations may be mixed with glycans and contain a variety of impurities. Secondly, as natural glycans, they may also cause biological side effects due to their inconsistent quality and traces of contamination. In search of substitutes, synthetic glycomimetics provide the compound more controllability over its structure. Glycomimetics have been shown to improve stability, bioavailability and half−life. Moreover, the activities of glycomimetics are comparable or even higher than their corresponding natural polysaccharides [65][29]. Based on this, Soria−Martinez et al. synthesized highly sulfated synthetic glycomimetics designed to mimic heparin and other natural polysaccharides with high sulfation degree as viral binding/infection inhibitors (Figure 4). The synthetic glycomimetics can effectively inhibit human papillomavirus (HPV16) infection in vitro and maintain the antiviral activity in vivo [66][30].
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Figure 4. A model of competition between sulfate−like polymers and cellular glycans to inhibit virus invasion.
In the molecular basis of influenza virus attaching to cell surface, the viral membrane protein hemagglutinin (HA) binds to the terminal sialic acid residues of cell surface glycoprotein. Therefore, inhibition of this interaction can effectively prevent influenza virus infection. Based on this, Watson et al. synthesized a glycopolymer of sialic acid and acrylamide, which combined sialic acid with HA to produce a blocking effect on the virus [67][31]. In addition, the glycopolymer can also block the contact between viruses and cells by steric effect. Similarly, Liu et al. prepared glycopolymers by reacting monomeric S−sialoside with polymers that contained maleic anhydride moieties [68][32]. Hemagglutinin and neuraminidase interact multivalently with mucin mimic glycoconjugates to inhibit viral infection. In addition, Li et al. synthesized sialyllactose−based glycopolymers by RAFT polymerization using a biotinylated chain transfer agent (CTA) and “post−click” chemistry [69][33] (Figure 5). The glyco−magbeads were obtained by reacting the biotinylated glycopolymers with Streptavidin magbeads, and they can be used to selectively capture influenza viruses.
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Figure 5. Chemical structures and schematic procedure for the preparation of the glyco−magbeads.
The blocking effect is influenced by a variety of parameters. In addition to the binding of specific sugars to viruses, the sugar density also affects their binding ability to viruses. Nagao et al. synthesized glycopolymers bearing sialyllactoses by “post−click” chemistry and evaluated their interaction with the influenza virus, and they proved that glycohomopolymers are not always the best structures, and the sugar density must be appropriate to exhibit a cluster glycoside effect as a result of a potential lack of flexibility [70][34]. Moreover, hemagglutinin has three binding sites on the surface, and the interaction between glycopolymers and the influenza virus will be enhanced if the polymer length is longer than the distance between the binding sites of hemagglutinin. Matsuoka et al. prepared sialyl α2 → 3 lactose(Slac)−based glycopolymer with acryl amide (AAm) as regulator for the arrangement of sugar density, and the glycopolymers showed inhibitory effects on the mumps virus [71][35] (Figure 6). The results showed that the glycopolymer with the lowest sugar density had the highest inhibitory capacity among three kinds of glycopolymers with 100%, 71.5% and 41% sugar contents. The results suggest that an appropriate distance between a sugar residue and the adjacent sugar residue in the glycopolymer is needed as the glycopolymer with the 41% sugar content is the most effective in binding MuV−HNs on the viral surface.
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Figure 6. Construction of a synthetic scheme for multivalent glycopolymer containing SLac part.
In addition, the topology of the glycopolymers has a significant impact on the binding ability of viruses. As shown in Figure 7, Nagao et al. synthesized a three−arm star−shaped glycopolymer containing sialyllactose based on the structure of HA with three sugar−binding pockets [72][36]. Precisely synthesized glycopolymers recognize HA on the surface of influenza viruses and interact with influenza H3N2. Among them, the interaction of the star copolymers with HA depends on the length of the polymer arm. When the hydrodynamic diameter of star copolymer and the distance between sugar−binding pockets of HA were comparable, the interaction of the star glycopolymers with HA was maximized.
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Figure 7. Topological design of star polymers with glycounits (left) and hemagglutinin (right).

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