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In-Depth Information
pathogens to the host's cell surfaces (Figure 4.3). The attachment is often a pre-
requisite for the later stages of infection, colonization and invasion of specifi c
human tissues. Due to their highly structured nature, their monodispersity and
their enhanced affi nities, glycodendrimers are therefore suitably designed for
inhibition of bacterial or viral adhesions to host tissues. Among the most inter-
esting cases, one can mention the use of mannosylated dendrimers as potential
ligands for fi mbriated
E. coli
, the major causative agent for urinary tract infec-
tions, and that it is responsible for serious nosocomial infections as it is the most
common cause of Gram-negative cystitis and pyelonephritis. This uropathogenic
bacterium possesses proteins at the tip of its fi mbriae (FimH) that recognize and
bind to mannosides of host human epithelial tissues as the premise for bacterial
infections. Many mannosylated dendritic structures with different scaffolds and
valencies having strong avidity for
E. coli
FimH have been proposed [15]. Early
work in this fi eld has shown that mannosylated dendrons built on
L
- lysine scaf-
folds (Figure 4.8) were rather potent inhibitors of attachment of
E. coli
to human
erythrocytes [4]. In 2007, the best ligands known to date were synthesized and
presented sub- nanomolar affi nities [18]. These tetrameric mannosides were 1000
times more potent than mannose for their capacity to inhibit the binding of
E. coli
to erythrocytes
in vitro
(for further examples of design of antibacterial
compounds, please see Chapter 17.3 ).
In addition, a wide range of immunodominant T- antigen - containing glycoden-
drimers have been synthesized, using nonimmunogenic scaffolds such as PAMAM
(Scheme 4.2 ) [19] . T - Antigen disaccharide (
-
D
- GalNAc) is charac-
teristic of certain cancer carcinomas, usually cryptic on healthy tissues and greatly
increased on breast and colorectal cancer cells as a result of aberrant glycosylation
of the
O
-linked sugars of mucins. The idea was to use such architectures described
in this chapter [neoglycoprotein (vaccine), glycopolymer (diagnostic) and glycoden-
drimer (therapeutic)] for interaction with carcinoma- related T - antigen - binding
receptors, among them galectins (please see Chapters 19 and 25) or to use them
for generation of T- specifi c antibodies for diagnostic and therapeutic purposes.
Results indicated a real dendritic effect going from G1 to G2 PAMAM dendrimer
(tetramer and 8-mer respectively); on a per-saccharide basis, the inhibitory effi cien-
cies of the dendritic structures were all similar and approximately 100 times better
than the monomer. Also, calix[
n
]arenes have proven effective as scaffold [20] .
In conclusion, numerous biological studies have shown that glycodendrimers
represent potent synthetic mimics of natural glycoconjugates and will interact
effi ciently with natural carbohydrate receptors, in many cases to an extent that
allows competition with natural binding substance as shown in this section.
β
-
D
- Gal - (1 - 3) -
α
4.8
Conclusions
Advances encountered in the fi eld of macromolecular chemistry in terms of isola-
tion, purifi cation and structural analyses have allowed the effi cient syntheses of
