Glycans are involved in a plethora of human pathologies including infectious diseases. Especially, glycosaminoglycans (GAGs), like heparan sulfate and chondroitin sulfate, have been found to be involved in different crucial stages of microbial invasion. Here, we review various therapeutic approaches, which target the interface of host GAGs and microbial proteins and discuss their limitations and challenges for drug development.

Introduction

Glycans represent one of the most diverse classes of biological macromolecules. They are a major part of the biomass of every organism and can be found within and outside of all living cells. Investigating the involvement of glycosylation, better called ‘glycanation’, in diverse biological processes has become a significant field in life science, particularly for targeting pathogens. Infectious diseases remain the primary cause of death, disability and social and economic disorder worldwide [1]. Pathogens have developed highly sophisticated tools to use host structures for invasion (as depicted in Figure 2). Especially, the glycosaminoglycans (GAGs), which are part of the cell membrane and the extracellular matrix (ECM), represent vulnerable targets for invading pathogens. Similarly, the exposed location of GAGs makes them easily amenable for therapeutic intervention.

GAGs are implicated in various steps during an infection. Many eminent pathogens like the Dengue virus [2] and Plasmodium falciparum [3] express GAG-binding proteins. These interactions affect almost all critical steps of microbial pathogenesis including host cell attachment and invasion, cell–cell transmission, dissemination and infection of secondary organs, and evasion of host defence mechanisms which have been covered by several excellent reviews [48].

Chemically, GAGs are linear polysaccharides, which are ubiquitously expressed by almost all mammalian cells. There are six representatives in this class of biomolecules, namely heparin (HP), heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and hyaluronic acid (HA) [9] (Figure 1). Except for HA, all GAGs are negatively charged due to the presence of varying amounts of sulfate and carboxyl groups within their structure (Figure 1). The position of these functional groups can vary, adding structural diversity. They are composed of repeating disaccharide subunits, which are made of an amino sugar and a hexuronic acid. These building blocks consist of variously N-substituted glucose- or galactosamine linked to glucuronic or iduronic acid [9].

Typical disaccharide composition of the GAG class members as discussed in the main text.

Figure 1.
Typical disaccharide composition of the GAG class members as discussed in the main text.

CS-A, HP, HA and HS. The sulfation and acetylation pattern can vary, as the chain length can.

Figure 1.
Typical disaccharide composition of the GAG class members as discussed in the main text.

CS-A, HP, HA and HS. The sulfation and acetylation pattern can vary, as the chain length can.

In mammals, GAGs are part of larger protein structures, the so-called proteoglycans (PG). PGs are decorated with typically more than one GAG chain from the CS, the HS or the KS type which are O-linked to serine residues of the core protein. These complex polysaccharides vary largely in their overall molecular mass, ranging from ∼30 kDa up to several hundred kDa, and they are involved in many physiological and pathophysiological processes [9]. HP and hyaluronan represent two specific forms of GAGs. HP is the only GAG which is not bound to PGs as it is released from serglycin by mast cells and is known for its antithrombotic effects. HA is the only GAG which is not sulfated and is well known for its water-binding abilities [9].

The cellular and tissue distribution of glycans in combination with specific sulfation patterns profoundly influence the interaction of a pathogenic agent with its host and distinguishes between health and disease. In many cases, GAGs act as an initial receptor increasing pathogen density and facilitating secondary receptor interactions (Figure 2, [8]). Several different strategies have been explored to target GAG–protein interactions in the context of infection including (i) enzymatic methods to remove or modify GAGs, (ii) the use of GAG mimetics to competitively block GAG–protein interactions and (iii) the utilisation of cationic proteins and peptides or small molecules to antagonise GAG–protein interactions.

How pathogens use PGs/GAGs for adhesion and invasion.

Figure 2.
How pathogens use PGs/GAGs for adhesion and invasion.

(A) GAGs as the first point of attachment; (B) GAGs as co-receptors facilitating closer contact to internalisation receptors; (C and D) Pathogens secret glycosidases or proteases which degrade GAGs chains or PGs and neutralise AMPs secreted by the host.

Figure 2.
How pathogens use PGs/GAGs for adhesion and invasion.

(A) GAGs as the first point of attachment; (B) GAGs as co-receptors facilitating closer contact to internalisation receptors; (C and D) Pathogens secret glycosidases or proteases which degrade GAGs chains or PGs and neutralise AMPs secreted by the host.

Although therapeutic antibodies (ABs) were already widely used for inhibiting protein–protein interactions, ABs raised against GAGs have so far been used mainly as research tools, for example, in histological studies (Table 1) [10,11]. Anti-GAG ABs have been investigated in some disease models (see Table 1), e.g. atherosclerosis [12,13], but their therapeutic utility in general and in particular for infectious diseases is limited mainly due to the generally high molecular dispersion of antigen preparations (i.e. GAG mixtures), against which these Abs were raised, which leads to low specificity and affinity and consequently to a low therapeutic efficacy.

Table 1
Selection of several ABs raised against different GAGs/GAG motifs
AB Antigen Methods applied Biological condition Source 
GD3A11 Highly sulfated CS-E subtype rich in GalNAc4S6S disaccharides ELISA Ovarian cancer [14
LKN1 4/2,4-di-O-sulfated DS domains IHC Renal pathology [15
GD3G7 CS-E IHC
Cell growth assay
Colony-forming assay 
Breast cancer [16
CS-56
2H6
MO-225 
CS -Octasaccharide
CS-A Octasaccharide
CS-D Octasaccharide 
IHC Neuronal development [17
HS3A8
HS3B7
HS4A5
HS4D4 
Bovine kidney HS
Human lung HS, mouse and human skeletal muscle HS 
ELISA (IC50)
IHC

 
Several

 
[18
AO4B08 N-sulfated octasaccharide with three consecutive 6-O-sulfates and an internally located 2-O-sulfate group IHC Neuronal development [19
HS4C3 HS from bovine intestine FC Bacterial invasion [20
10E4
3G10

 
N-sulfated glucosamine residue of HS
The non-reducing end of HS after digestion 
IHC Keratoconus [21
AB Antigen Methods applied Biological condition Source 
GD3A11 Highly sulfated CS-E subtype rich in GalNAc4S6S disaccharides ELISA Ovarian cancer [14
LKN1 4/2,4-di-O-sulfated DS domains IHC Renal pathology [15
GD3G7 CS-E IHC
Cell growth assay
Colony-forming assay 
Breast cancer [16
CS-56
2H6
MO-225 
CS -Octasaccharide
CS-A Octasaccharide
CS-D Octasaccharide 
IHC Neuronal development [17
HS3A8
HS3B7
HS4A5
HS4D4 
Bovine kidney HS
Human lung HS, mouse and human skeletal muscle HS 
ELISA (IC50)
IHC

 
Several

 
[18
AO4B08 N-sulfated octasaccharide with three consecutive 6-O-sulfates and an internally located 2-O-sulfate group IHC Neuronal development [19
HS4C3 HS from bovine intestine FC Bacterial invasion [20
10E4
3G10

 
N-sulfated glucosamine residue of HS
The non-reducing end of HS after digestion 
IHC Keratoconus [21

The majority was used as research chemicals (as mentioned in the text). Several of the ABs are also commercially available. Owing to the different methods applied, a comparison based on AB-antigen affinities is not possible.

IHC, immunohistochemistry; FC, flow cytometry.

Since the discussion of all glycans would go far beyond the purpose of the present work, we focus in this minireview on the O-linked GAGs involved in infection by Gram-negative and -positive bacteria, and which are also used by several human parasites. It should provide an overview of current therapeutic approaches (listed in Table 2) to target these microbial protein–glycan interactions and will additionally mention the role of GAGs in antiviral therapy.

Table 2
Compounds interfering with GAG-pathogen interaction
Substance Assay (including compound dose/dose range)* Pathogen References 
Cellulose sulfate Mouse infection model, MBC tests N. gonorrhoea [29
Polysodium 4- styrene sulfonate Mouse infection model, MBC tests N. gonorrhoea [29
Oxidised κ-Carrageenan MIC/MBC tests
1–13 mg/ml
Growth curve analyses 
Broad-spectrum antibacterial [41
Dextran sulfate Invasion and growth inhibition assay
1–25 mg/ml
Mouse infection model
2.5 mg/mouse 
T. gondii [70
Suramin Trypanosoma brucei [73
Fucoidans Mouse infection model
25–250 mg/kg/d 
L. donovani [80
Sevuparin Phase I/II
1,5–6 mg/kg/6 h 
Plasmodiae [90
VS1 Mosquito transmission blocking
500 µg/24 g BW 
Plasmodiae [88
GSII Cytoadherence inhibition assay
1 mg/ml 
Plasmodiae [92
FucCS Cytoadherence-, growth-, merozoite-, rosette-formation– inhibition assays
1–1000 µg/ml 
Plasmodium falciparum [93
EGCG Antiplasmodial activity assay
IC50 2.9 µM 
Plasmodium falciparum [94
Substance Assay (including compound dose/dose range)* Pathogen References 
Cellulose sulfate Mouse infection model, MBC tests N. gonorrhoea [29
Polysodium 4- styrene sulfonate Mouse infection model, MBC tests N. gonorrhoea [29
Oxidised κ-Carrageenan MIC/MBC tests
1–13 mg/ml
Growth curve analyses 
Broad-spectrum antibacterial [41
Dextran sulfate Invasion and growth inhibition assay
1–25 mg/ml
Mouse infection model
2.5 mg/mouse 
T. gondii [70
Suramin Trypanosoma brucei [73
Fucoidans Mouse infection model
25–250 mg/kg/d 
L. donovani [80
Sevuparin Phase I/II
1,5–6 mg/kg/6 h 
Plasmodiae [90
VS1 Mosquito transmission blocking
500 µg/24 g BW 
Plasmodiae [88
GSII Cytoadherence inhibition assay
1 mg/ml 
Plasmodiae [92
FucCS Cytoadherence-, growth-, merozoite-, rosette-formation– inhibition assays
1–1000 µg/ml 
Plasmodium falciparum [93
EGCG Antiplasmodial activity assay
IC50 2.9 µM 
Plasmodium falciparum [94

Abbreviations: MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration; BW, body weight.

*

For further details, please see references.

GAGs as therapeutic targets in infections caused by Gram-positive/Gram-negative bacteria

When bacteria reach their host organisms, they usually face a hostile environment with several mechanical protection mechanisms, such as shear stress, peristaltic motion and airway reflexes combined with inhabitable conditions like low pH-values. GAGs as molecular immobilisers, therefore, play an essential role for infectious microorganisms, which would be efficiently eliminated if attachment on host cells would be insufficient. Several strategies for inhibiting this bacterial protein–GAG interaction have therefore been applied in drug research and development. Some of those represent exciting approaches for novel antibiotics. In this chapter, we will present various bacteria and their targeted/targetable GAG interactions.

Chlamydiae are a group of obligate intracellular bacteria that infect humans in a variety of diseases. They are responsible for most bacterially related, sexually transmitted diseases (STDs) (Chlamydia trachomatis) in Western countries. They are also the cause of severe ocular and respiratory tract infections (Chlamydia pneumoniae). The interaction of these Gram-negative bacteria with GAGs is a key step in adhesion [22]. The specific involvement of the 6-O endosulfatases SULF1 and SULF2 [23] opens interesting possibilities for therapies against several STDs [22,23]. As in many approaches, targeting infected tissues without affecting healthy tissues remains a challenge.

Neisseria gonorrhoea is (together with Chlamydiae) the most common reason for STDs. The interaction of this Gram-negative bacterium with HSPGs is indisputably vital for its internalisation by the host. HSPGs act twofold: (a) as a co-receptor facilitating a beta 2-integrin bridge which induces internalisation [24]; (b) specifically the PGs syndecan 1 and 4 can also serve as a direct internalisation receptor [25]. Although cellulose sulfate [26], which like polysodium 4-styrene sulfonate [27] resembles certain GAG structures, failed in phase III clinical trials as vaginal HIV blocking agent [28], both compounds showed significantly high efficacy against N. gonorrhoea infections [29] (Table 2).

It has been shown that soluble GAGs can block in vitro the attachment to human cells of various bacteria. HP, LMW HP and CSA inhibited Chlamydiae infection of human epithelial HL and Hep-2 cells in a dose-dependent matter from 40 to 97% inhibition, whereas HP showed the best inhibitory effect [30]. For Listeriae, the attachment to and also the internalisation into HT-29 enterocytes was inhibited dose-dependently by HP, HS, CSA, CSB, CSC but not by HA [31] with the highest inhibition for HP. HS and a mixture of HS and CSA–CSC decreased adhesion of Staphylococcus spp. and Streptococcus spp. to A549 and MRC5 lung cells by ∼50% [32]. The HS/HP precursor heparosan, as well as HP itself, was found to block the adhesion of pathogenic Escherichia coli, Pasteurella multocida and Staphylococcus aureus to HT-29 colon carcinoma cells in vitro [33].

Translation of all these findings into novel therapeutics failed so far due to various effects of unfractionated, non-selective GAGs on the natural physiology. By binding to Antithrombin III (ATIII), HP and to a lesser extend HS tremendously decrease coagulation [34], and any therapeutic design targeting or using GAGs against infectious agents need to take this increased risk for bleeding into account. The use of anti-coagulative HP or HP-derivatives additionally carries the risk for HP-induced thrombocytopenia [35]. Both off-target effects represent major hurdles for drug development in the GAG field.

The biophysical properties, especially regarding hydrophilicity, anionic surface charges and high molecular mass of GAGs and GAG mimetics represent an additional obstacle for therapeutic targeting. Oral bioavailability for HP and HP-derivatives without special galenic formulations is close to zero so that only subcutaneous or intravenous application was proved to be useful [36]. Serum half-life of HP is ∼1.5 h after infusion due to various interactions with macrophages and endothelial cells [37]. However, the mentioned results nevertheless suggest a promising starting point for novel anti-infective therapies.

Since modified glycans, like K5-polysaccharide derivatives, were recently shown to be potent inhibitors of viral attachment [38], chemoenzymatic approaches to produce GAG analogues are a further path towards novel antibiotics. Similarly, carrageenans and fucoidans, isolated from marine organisms like seaweed and algae, are polysulfated polysaccharides which bind to GAG-binding proteins and thus antagonise pathogen-GAG interactions [39,40]. The antibacterial activity of carrageenans on S. aureus, Listeria monocytogenes, E. coli and Pseudomonas aeruginosa was recently investigated [41] and showed broad-spectrum antibacterial activity for oxidised κ-carrageenan (Table 2).

GAGs play an important role in pathogen Attachment. Moreover, they are used by microorganisms to evade the host immune system. AMPs are antimicrobial peptides which play an essential part in the innate immune defence among many microorganisms. The cationic versions of these peptides, like defensins and cathelicidins, can disrupt the lipid membranes of various pathogens including Gram-positive and Gram-negative bacteria [42]. Since these AMP show a high density of positive charges, the idea that microorganisms exploit host-derived GAGs to inhibit the activity of AMPs is evident. Schmidtchen et al. showed this mechanism of action for P. aeruginosa, Enterococcus faecalis and Streptococcus pyogenes, which secrete proteinases to degrade the PG decorin in the ECM which consequently leads to the release of soluble, AMP-neutralising DS fragments [43].

Additionally, induced PG shedding from human host cells was found for Streptococcus pneumoniae via ZmpC metalloproteinase [44] and for P. aeruginosa [45], two primary causative agents of pneumonia. P. aeruginosa is a Gram-negative, opportunistic bacterium causing life-threatening infections in pathological conditions of epithelial injury, especially in cystic fibrosis [46]. Park et al. demonstrated reduced P. aeruginosa infection in vivo in an intranasal lung infection model by applying the cationic macromolecule protamine [45]. Protamines are arginine-rich proteins isolated from salmon sperm and other fish, which are interpreted to reverse the neutralising activity of shed GAGs on AMPs. Protamines are, despite several possible side effects, the only clinically approved medicines to reverse HP toxicity [47].

Antibacterial activity has also been found for GAG-binding, chemokine-derived peptides, particularly CXCL8 [48], as reviewed in [49], the involvement of GAGs, as well as a therapeutic utility, being not clear in every case. To explore this approach further, the specificity of chemokine–GAG interactions needs to be investigated in more detail since typically more than one chemokine is involved in an immunological reaction to pathogen invasion (CXCL8 being only one of them). Particularly as an add-on therapy to other (conventional) antimicrobial therapies, chemokine-derived GAG-targeting peptides could be of great interest as immune modulators before, during and after infection.

Another cationic peptide, namely Melittin [50], was found to bind GAGs [51] and thereby exerts antibacterial activity [52]. Compounds that antagonise GAG–protein interactions by a high positive charge density, as lactoferrins have also been reported to have antimicrobial [53] and antiviral [54,55] properties. Novel HP antagonists [5659] are currently under preclinical or clinical investigation, which represent an additional potential source for novel antibacterial substances. As an example in which GAG binding negatively influences antibacterial activity is the human cationic peptide AMP LL-37 which has the ability to neutralise LPS [60]. The interaction of AMP LL-37 with GAGs and DNA inhibits its antibacterial effects and leads to chronic infections, especially in patients suffering from cystic fibrosis.

Several small-molecule GAG antagonists (MW < 900 Da) have antiviral properties against herpes simplex type 1, hepatitis C virus, respiratory syncytial virus and human cytomegalovirus [6163]. Since substances like the dispirotripiperazine derivative DSTP-27 or epigallocatechin gallate [63,64] have not been tested against bacteria yet, an additional antibacterial activity of these compounds which target HS cannot be excluded.

In summary, the antibiotic properties of native GAGs, GAG mimetics, peptides and low molecular mass GAG-inhibitors represent a valuable source for potentially novel antibiotics. Broad off-target effects and toxicity are major obstacles in an in vivo implementation. Drug development targeting or using GAGs additionally needs to prove a better therapeutic utility than current antibiotics. Nevertheless, a growing interest has thus become the identification of novel GAG-binding proteins from bacteria which represent natural targets for antimicrobial therapeutic approaches.

Our group has recently identified novel GAG-binding proteins from Moraxella catarrhalis, a gram-negative bacterium causing otitis media mainly in children [65], by a GAG-mediated pull-down proteomic approach. By this means, several new GAG-binding proteins have been found which represent interesting targets for drug and vaccine development. Previously, Gesslbauer et al. have investigated the GAG-binding membrane proteome of three different Borrelia species [66]. This study revealed 32 unique surface-exposed proteins binding to HP that are of high interest for establishing prevention and treatment of Lyme disease (LD). LD is a tick-borne illness in which the bacteria colonise the ECM of many organs. For this colonialisation, one protein is highly critical, namely the decorin-binding protein A (DbpA), which has been shown to be a potent GAG binder [67]. DbpA is a surface lipoprotein, exclusively expressed during the human infection stage but with a high genetic variation between strains, which mainly influences the GAG-binding ability of the two known isoforms [67].

GAGs as therapeutic targets against human parasites

As for bacteria, many parasitic protozoa use GAGs for host recognition, attachment and invasion. The genus of Toxoplasma gondii, for example, causes toxoplasmosis, which is the most prevalent protozoic infection among humans and domestic animals. The parasites produce HP- and HS-binding lectins in the tachyzoite stage with GAG-binding specificity, whereas the involvement of GAGs in the lifecycle of the parasite is not clear yet [68,69]. The protozoic proteins ROP2, ROP4 as well as GRA2 and SAG1 were shown to bind differently sulfated GAGs and HP oligosaccharides, with unique specificities found for varying N-/O-sulfation [69]. The discovery that even high concentrations of free HP, HS or CS were not able to inhibit the invasive processes due to an alternative sialic acid-dependent pathway [69,70], only showed how multifaceted the parasite's invasion machinery is. Ishiwa et al. were able to inhibit T. gondii infections in vitro by using low molecular mass dextran sulfate (Table 2), which is supposed to work either by a direct interaction between the host and the parasite or indirectly via a yet unidentified pathway [70].

The unicellular parasite, Trypanosoma cruzi, causes American trypanosomiasis, also known as Chagas disease, which affects ∼ 6–7 million people worldwide, mostly in Latin America. It was shown that the parasite uses HS and CS present on the luminal surface of its vector Rhodnius prolixus [71] and mammalian host cells [72], indicative for a different GAG-binding profile of vector and host stage. Another species of the Trypanosoma genus, T. brucei, is the causative agent of the African trypanosomiasis or sleeping sickness. Although no GAG binding for T. brucei has been published, the first-line treatment for sleeping sickness (not involving the nervous system) is the polysulfonated substance suramin [73] which displays typical GAG features. Additionally, HS directly influences the activity of a promising drug target, the T. brucei cysteine protease brucipain [74].

The genus of the intracellular Leishmania parasites is responsible for several million cases of Leishmaniasis every year. For several parasite species, a GAG-dependency has been shown [7577]. Interestingly, CS is used to detoxify the second-line treatment of Leishmaniasis, amphotericin B, in a specialised nano-formulation [78,79]. Furthermore, GAG analogues derived from brown algae, the so-called fucoidans (see above), showed an inhibitory effect on L. donovani (Table 2) [80].

Five members of the Plasmodiae are responsible for malaria disease in humans. Plasmodium vivax, P. ovale, P. malariae, P. knowlesi and P. falciparum cause a worldwide estimated number of 214 million cases annually [81]. These infections leave 438 000 people dying from the parasites, with ∼3.2 billion people, almost the half of the world's population living with the risk of malaria [81]. Plasmodia encounter a large number of GAG-presenting barriers during its life cycle, involving different organs as well as a change of host. The parasite adopted during its evolution a host-invasion system which uses various GAG structures [8287] very efficiently. Several approaches taking advantage of these interactions to target the parasite in anti-malarial treatments — especially P. falciparum — have been published.

Mathias et al. produced and tested a transmission-blocking agent based on vinyl sulfonic acid (Table 2) [88]. VS1 is a synthetic sulfonated polymer aimed to inhibit the interaction of the sexual stage ookinetes with CS PGs in the mosquito's midgut wall [88], thereby blocking malaria transmission. Since HP was already used as adjuvant therapy in malaria treatment but was discontinued due to severe side effects, several groups aimed for HP analogues without antithrombotic effects. In 2006, Vogt et al. reported the development of modified heparins (dGAGs) which not only efficiently block merozoite invasion, but also disrupt erythrocyte rosettes, inhibit endothelial binding of infected erythrocytes, and reverse sequestration without showing significant anti-coagulation [89]. These and other data resulted in the development of Sevuparin (Table 2) which is currently investigated in clinical trials as an adjuvant therapy for uncomplicated malaria [90,91].

Other semi-synthetic GAG analogues were recently tested in vitro by Skidmore et al. for their antiplasmodial activity [92]. These authors were able to show reduced binding of differently infected erythrocytes to several cell lines under physiological flow conditions. The most promising drug candidate GSII demonstrated significant efficacy in inhibiting cytoadherence under static and flow conditions without exhibiting cytotoxicity or anti-coagulative effects [92].

A fucosylated CS (FucCS), isolated from sea cucumber, also efficiently blocked cytoadhesion from P. falciparum-infected erythrocytes to human lung endothelial cells, in which case the fucosylation seemed to be the key for antiplasmodial activity (Table 2) [93]. Additionally, the FucCS inhibited merozoite invasion and disrupted erythrocyte rosettes [93]. The GAG-antagonist Epigallocatechin-3-gallate (EGCG) isolated from green tea was shown to bind to PfHSP70 and inhibit the growth of 3D7 P. falciparum in vitro (Table 2) [94], which points out further to yet unexplored small molecules interfering with plasmodial-GAG interactions. A slightly different approach for anti-malarial drugs based on interfering with glycan synthesis was recently discussed by Gomes and Morrot [95].

GAGs as therapeutic targets in fungal infections

Although distinct GAG-binding properties for Candida albicans are described in the literature [96,97], so far no antifungal drug targets based on GAGs have been developed or tested. It is not unlikely that several of the substances and approaches mentioned in the chapters above can also provide suitable ways for challenging fungal diseases.

Conclusion

Owing to their crucial involvement in many steps of microbial and parasite invasion of human tissues, as we have tried to outline in the paragraphs above, GAGs are becoming increasingly important as targets for drug and vaccine development. Based on their complex nature, efficient therapies will ultimately depend upon our deeper understanding of the structure–function relationship of GAGs and the specificity by which they are recognised by their cognate proteins, as well as on the ability to (bio) synthesise well-defined GAG oligosaccharides with low risk for off-target effects.

Abbreviations

     
  • AB

    antibodies

  •  
  • AMP

    antimicrobial peptides

  •  
  • CS

    chondroitin sulfate

  •  
  • DbpA

    decorin-binding protein A

  •  
  • DS

    dermatan sulfate

  •  
  • ECM

    extracellular matrix

  •  
  • FucCS

    fucosylated CS

  •  
  • GAG

    glycosaminoglycan

  •  
  • HA

    hyaluronic acid

  •  
  • HP

    heparin

  •  
  • HS

    heparan sulfate

  •  
  • KS

    keratan sulfate

  •  
  • LD

    Lyme disease

  •  
  • PG

    proteoglycan

  •  
  • STD

    sexually transmitted diseases

Author Contribution

The idea and conceptual design for the paper as well as the concluding remarks came from A.J. Kungl. J. Almer was responsible for the main text and the literature research. B. Gesslbauer provided background research.

Funding

The present work was partly funded by the University of Graz and partly by Antagonis Biotherapeutics GmbH.

Acknowledgments

The authors thank the members of our group for stimulating discussions and valuable intellectual input.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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