Chemistry Reference
In-Depth Information
thesis of multivalent carbohydrate ligands is likely to remain the method of choice
to afford various well- defi ned architectures that have been developed as effectors
or inhibitors of biological mechanisms. Thus, synthetic analogs (neoglycoconju-
gates) in which carbohydrate residues are chemically or enzymatically attached to
unnatural carriers present numerous advantages. Moreover, using structure-
activity relationships, it is also possible to identify many of the essential carbohy-
drate residues (epitopes) responsible for the biological activity of interest (for
further details, please see Chapter 14). One can consider that neoglycoconjugate
syntheses are facilitated by simpler carbohydrate targets (for further details, please
see Chapter 3). Progress encountered in terms of their synthetic accessibility and
effi ciency has allowed their modulation and their activity optimization remains
necessary to investigate how these multivalent structures can infl uence the binding
activity. These investigations are critical to highlight the potential of multivalent
carbohydrate inhibitors as high- affi nity ligands or as effectors capable of clustering
cell-surface receptors and may lead to generate structures with tailored biological
activities.
This section will be dedicated to the description of the multivalent neoglycocon-
jugate family, emphasizing the preparation of glycomimetics of prominent
components at the surfaces of mammalian cells (that is neoglycoproteins, neogly-
colipids), and the synthesis of glycopolymers and glycodendrimers, briefl y men-
tioning their respective uses in biomedical applications (for further information,
please see Chapters 24 - 30 ).
4.3
Neoglycoproteins
Neoglycoproteins represent the fi rst class of synthetic neoglycoconjugates since
they were initially synthesized as capsular polysaccharide protein conjugate vac-
cines related to pneumococcal infection [5]. Nowadays, several reasons and
methods to generate neoglycoproteins exist, and the need for neoglycoproteins
stems from the lack of carbohydrate homogeneity in natural glycoproteins. It has
also been observed that certain threshold carbohydrate contents were necessary
for the expression of desired biological activities, and one way to remedy this situ-
ation was to artifi cially introduce more and even unnatural carbohydrate moieties.
Therapeutic glycoproteins such as antibodies recently need to be ' glycoengineered '
for medical approval. Naturally occurring carbohydrates are linked to proteins via
an
N
-glycosidic bond to the side-chain of asparagine or an
O
- glycosidic bond to
hydroxylated amino acids serine and threonine (for further details on
N
- and
O
-
glycan attachment, please see Chapters 6-8). Table 4.1 lists a few of the possible
amino acid modifi cations by carbohydrates derivatives for neoglycoprotein
synthesis.
Combined with site-directed mutagenesis, this approach allows control of both
the site of attachment and choice of saccharide introduced. Furthermore, a mixed
strategy of an initial linear assembly coupled with convergent build- up, involving
