CLICK CHEMISTRY APPLIED TO CARBOHYDRATE-BASED DRUG DISCOVERY - Click Chemistry in Glycoscience: New Developments and Strategies - page 325

recognition activities were investigated using surface plasmon resonance (SPR) bind-
ing assays [27]. The sulfated-galactose multivalent construct 42c showed the highest
binding affinities to L- and to P-selectin, with IC 50 values of 1 and 7 nM, respectively.
This result corroborates prior findings that polyanionic carbohydrate ligands display
marked binding enhancement to selectins [28].
13.3 CLICK CHEMISTRY AND GLYCOCONJUGATE
ANTITUMOR VACCINES
Reverse vaccinology comprises an innovative approach involving the recognition and
characterization of key epitopes on selected antigens, which are bound by neutralizing
or inhibitory antibodies, later on used for guiding effective vaccine design. Once the
target is established, small and synthetically accessible planned structuresmay be built
mimicking only important epitopic regions, which allows focusing on the immune
reaction [29]. Hence, the role played by chemical synthesis in the rational design and
optimization of therapeutic agents able to interfere in the immune response processes
is of great relevance. [29].
Regarding tumoral antigens, carbohydrates are considered the most important
targets for inducing active immunity, considering that they are found in several O -
glycosylated mucin glycoproteins and glycolipids expressed on a variety of tumor
types, acting as broad-spectrummarkers associated with malignancy [30]. Therefore,
several tumor-associated glycoprotein and glycolipid antigens, such as the mucin-
O -linked truncated glycans Tn, sialyl-Tn (STn), and Thomsen-Friedenreich (TF), as
well as the lipid tail-containing Globo-H, gangliosides (GM2, GD2, GD3), and Lewis
(X, Y), have been adopted as targets for the development of therapeutic vaccines
against cancer [31].
Antigenic carbohydrates alone trigger a T cell-independent immune response
through direct activation of B lymphocytes, resulting in the production of low affinity
IgM antibodies, solely. Thus, application of carbohydrates as vaccines is conditioned
to their coupling to immunogenic carrier proteins or peptides, such as bovine serum
albumin (BSA) and keyhole limpet hemocyanin (KLH). Such approach ensures the
stimulation of T lymphocytes, which do not recognize intact antigens but are sensi-
tized by antigenic peptide fragments processed and presented viaMajor Histocompat-
ibility Complex [32]. Another strategy to improve immunogenicity of carbohydrate-
based vaccines involves the concept of multivalency tomimic more properly the dense
display of carbohydrates on cell surfaces. Tumor-associated carbohydrate antigens
grouped in dendrimers or clusters are then far more efficient in eliciting a protective
response than the isolate analog [33].
Cu(I)-assisted 1,3-dipolar azide-alkyne cycloaddition (CuAAC) reactions have
been largely applied for the development of neoglycopeptides containing the tria-
zole moiety as synthetic antitumor vaccines. Taking into account the well-known
difficulties found in traditional solid phase synthesis (SPS) procedures for joining
oligosaccharides to polypeptides, the use of click reactions has proved to be advan-
tageous for synthesis of complex glycopeptides via coupling of azide-containing