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Figure4.11 Self-adjuvanting strategy.
(a) (b)
Figure4.12 Chemical structures of adjuvant–antigen complexes. (a) MPL conjugated
with α-2,9-oligosialic acid. (b) RC-529 conjugated with a Thomsen— Friedenreich antigen.
(c) RX-527 conjugated with peptide antigen.
References
4.9 Conclusions
In this chapter, the structure–activity relationship of TLR4ligands, especially of
lipid As, and their potential as vaccine adjuvants have been discussed. Similar to the
case of MPL and parasitic bacterial lipid As, structural modifications can regulate
the activation of the TLR4/MD2 receptor and selective induction of intracellular
signals. Therefore, cell-mediated, humoral, or mucosal immune responses can be
controlled using a specific lipid A derivative. Various lipid A derivatives, mainly
MPLs, are being developed as adjuvants, and next-generation safe adjuvants such as
symbiotic bacterial lipid A also show great potential. Since the clinical use of lipid
A-based adjuvants, including the AS series (GSK), has already been expanding in
development as components of various novel vaccines such as anticancer vaccines
and antiprotozoal vaccines, including antimalarial vaccines, the importance of lipid
A adjuvants will increase in the future. The development of a self-adjuvanting strategy that can further enhance the function of lipid A adjuvants is also expected. In
contrast, lipid A activity is significantly affected by subtle differences in its chemical
structure, that is, the balance between the hydrophobic region formed by fatty acids
and the hydrophilic region formed by sugar moieties, the number and position of
phosphate groups, and the addition of Kdo. Hence, it is difficult to modify lipid A
while retaining its immune function. Once a simple and universal lipid A modification method that can retain its function has been developed, it will be a breakthrough in developing innovative self-adjuvanting vaccines.
127
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5
Antiadhesive Carbohydrates and Glycomimetics
Jonathan Cramer
1
University of Basel, Department of Pharmaceutical Sciences, Pharmacenter, Klingelbergstrasse 50, Basel
CH-4056, Switzerland
2
Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1,
Düsseldorf DE-40225, Germany
3
WuXi AppTec UK LTD, 5 New Street Square, London EC4A 3TW, United Kingdom
1,2
, Lijuan Pang3, and Beat Ernst
1
5.1 Introduction
Infectious diseases are still a major cause of death, disability, and social and economic
disorder for millions of people throughout the world. Poverty, poor access to health
care, human migration, emerging disease agents, and antibiotic resistance all contribute to the expanding impact of these illnesses[1]. Prevention and treatment strategies
for infectious diseases are derived from a thorough understanding of the complex
interactions between specific viral or bacterial pathogens and the human host.
Glycans are found on the surfaces of all bacteria and viruses, as well as on their
hosts. Thus, a majority of interactions between microbial pathogens and their hosts
are based on the interaction of carbohydrate epitopes on the one hand and glycanbinding receptors on the other hand[2]. This initially leads to the colonization of
host epithelial surfaces, a prerequisite for spreading infection. In this chapter, the
status of the development stage of Antiadhesive Carbohydrates and Glycomimetics is
presented by means of some selected examples.
131
5.1.1 Carbohydrate–Protein Interactions inViral Adhesion
toHost Cells
The surfaces of viruses and host cells are densely covered with diverse glycans. Many
viruses exploit carbohydrate–protein interactions for adhesion to host cells, initiation of
virus internalization, and evasion of immune surveillance[3–5]. Whereas bacterial adhesion is most commonly mediated by the interaction of bacterial lectins with host-derived
glycoproteins, viruses have a more diverse arsenal of adhesion mechanisms. Similar to
bacteria, some viral pathogens display carbohydrate-binding proteins on their surface
that can specifically recognize certain host glycans [5]. A well-studied example is the
interaction of the hemagglutinin glycoprotein expressed on the surface of influenza
Carbohydrate-Based Therapeutics, First Edition. Edited by Roberto Adamo and Luigi Lay.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
5 Antiadhesive Carbohydrates and Glycomimetics
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132
A viruses with sialic acid-containing host glycans. Furthermore, glycosaminoglycans,
acidic linear polysaccharides that commonly decorate host cell surfaces, can serve as an
initial attachment factor for many different viruses. Alternatively, endocytic carbohydratebinding receptors on host cells can promote adhesion to viral envelope glycoproteins and
subsequent internalization[3, 4]. An archetypical example of this process, the interaction
of the myeloid C-type lectin DC-SIGN with viral glycoproteins, will be discussed in this
book chapter. Many viruses employ different strategies for adhesion simultaneously.
Besides mediating the interaction with sialic acid receptors, the influenza A hemagglutinin glycoprotein is also heavily modified with N-linked glycans. These structures are recognized by DC-SIGN and mediate a secondary, sialic acid-independent adhesion and
entry mechanism into host cells[6].
5.1.2 Bacterial Adhesins and Antiadhesion Therapy
An essential step of bacterial infection and pathogenesis is the adherence of bacteria
to cell surfaces of the host tissue, granting the bacteria substantial resistance to natural defense mechanisms, mechanical shear stress, and antibiotics[7]. Bacteria can
express more than one type of adherence factors or “adhesins.” Most of these adhesins are lectins that bind directly to cell-surface carbohydrate motifs on glycoproteins
or glycosphingolipids via carbohydrate-recognition domains (CRDs)[8, 9]. Bacterial
lectins commonly exist in the form of elongated, hair-like, multi-subunit protein
appendages, known as fimbriae (hair) or pili (threads), protruding from the surface
of bacteria[7, 8]. Although carbohydrate–lectin interactions are generally of low
affinity, such pili structures provide a multivalent, Velcro-like binding to epithelial
surfaces, hence facilitating bacterial survival and invasion[8, 10]. Therefore, antiadhesive agents that block bacterial adherence to host tissues may offer a novel strategy to combat infectious diseases.
Similar to animal lectins, bacterial lectins bind to terminal sugar residues or internal glycan sequences present in linear or branched oligosaccharide chains [11].
Since Sharon etal. first described bacterial surface lectins in 1970s,[12] researchers
have identified a large fraction of the carbohydrate epitopes (“adhesin receptors”)
used by bacteria for colonization and entry into host tissues (Table 5.1) [31].
Although the natural carbohydrate epitopes show effectiveness in blocking microbial adhesion, their susceptibility to enzymatic degradation and undesirable pharmacokinetic properties hamper their clinical applications [32]. Based on resolved
protein structures, structure-based rational design advanced the identification and
optimization of antiadhesive glycomimetics, allowing improved metabolic stability,
binding selectivity, and bioavailability[33–35]. In the era of increasing antimicrobial resistance, one exceptional advantage of antiadhesive therapeutics is that they
do not kill or restrict the growth of the pathogens and are therefore less likely to
promote antibacterial resistance. Additionally, antiadhesive agents could potentially reduce overuse of broad-spectrum antibiotics and thus prevent long-lasting
detrimental effects on the healthy human microbiota. Furthermore, target-specific
antiadhesion therapy makes precision antimicrobial treatment possible [36, 37].
The search for FimH and PA-IL/IIL inhibitors depicts representative examples of
modern antiadhesive therapeutics.
5.2 DC-SIGN-Mediated Viral Adhesion and Entry into Myeloid Cells
5.1.3 Selected Examples
In this chapter on Antiadhesive Carbohydrates and Glycomimetics, we are forced to
limit ourselves to a few selected examples. From a plethora of therapeutic targets for
which the involved carbohydrate ligands and lectins have been elucidated, only the
most prominent examples, namely DC-SIGN and the virulence factors FimH, PA-IL,
and PA-IIL, were selected for discussion.
The C-type lectin receptor DC-SIGN is a pattern recognition receptor expressed
on macrophages and dendritic cells (DCs). It has been identified as a promiscuous
entry receptor for many pathogenic agents, including pandemic viruses such as
SARS-CoV-2, ebola, and HIV[38]. The virulence factors FimH, PapG, PA-IL, and
PA-IIL are expressed by pathogenic bacteria that represent an immediate or future
threat to public health in the light of emerging antibiotic resistance.
FimH is one of the most studied adhesins expressed by uropathogenic Escherichia
coli (UPEC) strains because it is a key determinant of urovirulence [39]. Urinary
tract infections (UTIs) and catheter-associated urinary tract infections (CAUTIs) are
becoming increasingly important threats to human health, and the antiadhesive
strategy emerged as a relevant alternative therapeutic approach. Recently, the FimH
antagonist GSK3882347 entered Phase I clinical trials in a collaboration between
Fimbrion Therapeutics and GlaxoSmithKline.
Finally, Pseudomonas aeruginosa produces biofilms that can cause chronic opportunistic infections, which often cannot be treated effectively with traditional antibiotics [40]. Since P. aeruginosa is considered a model organism for the study of
antibiotic-resistant bacteria, its virulence factors PA-IL and PA-IIL were extensively
studied.
133
5.2 DC-SIGN-Mediated Viral Adhesion and Entry into
Myeloid Cells
5.2.1 Introduction
C-type lectin receptors (CLRs), a class of proteins expressed on the membrane of
myeloid cells such as DCs and macrophages, are often exploited as entry receptors
by viral pathogens[38, 41]. Physiologically, CLRs recognize conserved carbohydrate
epitopes on diverse pathogens and initiate tailored immune responses. However,
some viruses have developed the ability to circumvent the physiological function of
CLRs and infect myeloid cells themselves (cis-infection) or other cells under mediation of myeloid CLRs (trans-infections). The CLR DC-specific ICAM-3-grabbing
nonintegrin (DC-SIGN, CD209) has been proven vulnerable to viral exploitation,
most famously in the pathology of HIV infections[38, 41–43]. DC-SIGN-mediated
adhesion and internalization of virus particles can result in trafficking to nonlysosomal compartments and virus persistence in a protected intracellular environment.
viruses, such as dengue, zika, ebola, and coronaviruses [38]. Because of their
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134
Table5.1 Carbohydrate epitopes used by bacteria for colonization and entry in host
tissues.
Pathogen Adhesin Binding epitope References
Campylobacter
jejuni
Escherichia coli Type-1 fimbriae Manα(1-3)Manα(1-6)Man [14]
Haemophilus
influenzae
Helicobacter pylori BabA Lewis B [21]
Klebsiella
pneumoniae
Mycobacterium
tuberculosis
Neisseria
gonorrhoeae
Pseudomonas
aeruginosa
Salmonella
typhimurium
Streptococcus
pneumoniae
Streptococcus suis SadP Galα(1-4)Galα(1-4)Glc [30]
Flagella, LPS Fucα(1-2)Galβ(1-4)GlcNAc [13]
P fimbriae Galα(1-4)Gal [15]
S fimbriae Neu5Acα(2-3)Galβ(1-4)
K99 fimbriae Gangliosides GM3,
CFA1 AsialoGM1, Lewis A [18, 19]
HMW1 adhesin Neu5Acα(2-3)Galβ(1-4)
SabA Sialyl Lewis X [22]
Type-1 fimbriae Man [23]
Heparin-binding
hemag-glutinin adhesin
(HBHA)
Opa proteins LacCer, Neu5Acα(2-3)
PA-IL (LecA) Galactosides [26]
PA-IIL (LecB) Lewis A, Fuc [27]
Type-1 fimbriae Man [28]
Carbohydrate-binding
modules of
β-galactosidase, BgaA
GalNAc
Neu5Glcα(2-3)Galβ(1-4)Glc
GlcNAc
Heparan sulfate [24]
Galβ(1-4)GlcNAc, syndecans,
heparan sultate
Lactose, N-acetyllactosamine, Neu5Acα(2-3)
Gal
[16]
[17]
[20]
[25]
[29]
potential to interfere with viral adhesion, carbohydrate-based molecules and glycomimetic drugs targeting DC-SIGN are of tremendous interest. This treatment strategy circumvents common resistance mechanisms through attenuation of virulence
and provides a host-directed pharmacological response to not only established but
also newly emerging infections with pandemic potential.
DC-SIGN is anchored to the cell membrane by a hydrophobic neck domain that
induces tetramerization (Figure5.1a). Carbohydrate ligands are bound to the CRD
by a calcium ion acting as a cofactor in the primary binding site (Figure 5.1b).
5.2 DC-SIGN-Mediated Viral Adhesion and Entry into Myeloid Cells
(a) (b)
Figure5.1 Structure of DC-SIGN. (a) Schematic depiction of DC-SIGN domain organization.
(b) The carbohydrate-binding site of DC-SIGN in complex with α-1,2-mannobiose (PDB
2IT6). Secondary interaction sites commonly targeted by glycomimetics are highlighted.
DC-SIGN naturally binds to underprocessed high-mannose-type glycans (e.g.
GlcNAc2) that are abundantly presented on viral envelope glycoproteins.
Man
9
Fragments of this glycan as well as mannose itself also bind to DC-SIGN, albeit with
lower binding affinity. In addition, DC-SIGN recognizes fucosylated glycans such as
Lewis-type and ABO antigens. Canonically, mannose or fucose epitopes coordinate
with the central calcium ion via their 3-OH and 4-OH groups[44, 45]. However, it
has been demonstrated that mannose ligands are able to bind in a variety of transient binding modes, also employing other hydroxyl functions [46]. Various concepts have been employed to identify glycomimetic ligands that utilize secondary
binding sites to achieve higher monovalent affinity toward DC-SIGN. Besides
ligand-/structure-based design[47, 48], combinatorial[49, 50] and fragment-based
approaches[51, 52] were successful. Important sites for additional secondary interactions in an extended binding site are highlighted in Figure5.1: In the long loop,
Val351mediates binding of Lewis-type antigens to DC-SIGN[45, 53]. A hydrophobic subsite in the vicinity of Phe313 is an additional target for glycomimetics[52,
54]. This allosteric pocket, as well as several other distal areas, have been identified
as binding sites for noncarbohydrate fragments. Finally, Glu358 and Ser360have
been shown to act as binding partners for positively charged residues[47]. In general, druggability of DC-SIGN and other CLRs has been soundly demonstrated by
experimental and computational approaches[51].
Approaches for the development of carbohydrate-based inhibitors of viral attachment and entry can be categorized into two different groups. Firstly, natural monoor oligosaccharide ligands of DC-SIGN have been utilized for the synthesis of
various multivalent systems. A second approach relies on the design of carbohydrate derivatives or glycomimetics that surpass the affinity of natural ligands and
can be employed as monovalent therapeutics or utilized for the construction of multivalent systems with improved affinity.
135
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