Since glycans play an important role in
intercellular interactions and protein, they serve as viable
targets for various therapeutic interactions. Multiple current therapeutics aim to take advantage of their role in signaling pathways, and target their biosynthesis or engineer related glycoproteins. These interactions can be controlled by encouraging or inhibiting the presence of those glycans that mediate signaling, which is the
mechanism of action for a number of extant drugs, including
heparin,
erythropoietin, the antivirals
oseltamivir and
zanamivir, and the
Hib vaccine. Furthermore, the glycans themselves can serve as drugs and there is ongoing research and development to engineer more effective ones.
Drug targeting The surfaces of cancer cells often exhibit aberrant
glycosylation, which serves to mediate
cell proliferation,
metastasis, and
tumor progression. However, because these glycans often differ from those present on healthy cells, they also serve as candidates to act as
cancer biomarkers for use in diagnostics and in developing targeted therapies that discriminate between cancerous cells and normal host tissue. One such therapy involves the use of
enzyme inhibitors that target those enzymes involved in the biosynthesis of cancer-associated glycans. Another treatment is
cancer immunotherapy, which directs the immune system to attack tumor cells expressing the targeted
altered glycoconjugates. For example, modifying
CD44 antigens using glycosyltransferase-programmed stereosubstitution (GPS), the
HCELL expression on the surfaces of human
mesenchymal stem cells and
hematopoietic stem cells can be enforced, effectively
homing those cells to the bone marrow of their host. Once mesenchymal stem cells transmigrate through the bone marrow
endothelium, they differentiate into
osteoblasts and begin contributing to
bone formation. This technique has been proposed as a potential treatment for numerous bone diseases, including
osteogenesis imperfecta. Other therapeutic measures involving glycans include
epitope recognition for both
vaccine and
antibody production. This has been an area of interest especially in the field of
HIV vaccines, as the immense genetic diversity of strains and high degree of glycosylation leads to much difficulty in developing antibodies that bind to viral particles. The heavy glycosylation of these proteins can mask peptide epitopes, making designing antibodies targeted to certain proteins sections all the more difficult. Therefore, some have turned to translational glycobiology to develop antibodies using semi-synthetic and fully synthetic oligosaccharides as
antigens. Many of these discoveries have focused on the
GP120 surface
glycoprotein, which is naturally heavily glycosylated with high mannose glycans. Glycans can interact with
receptors, which in turn affect their cellular and
subcellular localization. For example,
cytokines and the subgroup
chemokines are small signaling proteins that are involved in the
immune response. Many of the
N-linked glycans on these cytokines play an important role in metabolic turnover and by engineering the glycoform and its branching, there can be advantageous
physiochemical affects on the immune response. Furthermore, glycosylated proteins, or glycoproteins, can have increased resistance to degradation by
proteases, which will increase the
half-life of those proteins. For example,
interferon beta has been shown to be important in the treatment of
multiple sclerosis.
Recombinant versions of interferon beta have been produced in
Escherichia coli, with the glycosylated form being more stable and resistant to protease degradation, while the non-glycosylated form is degraded much more quickly. Engineered glycoproteins have also been instrumental in
enzyme replacement therapy (ERT). This has been of particular interest in the development of therapeutics for
lysosomal storage disease. Proper delivery of these enzymes is highly dependent on the
mannose 6-phosphate (M6P) tagging on N-glycans. Thus, engineering of these N-glyans, such as by modification of branching patterns,
sialic acid capping, M6P tagging, monosaccharide constituents, and
glycosidic bond linkage, there can be increased efficacy of lysosomal targeting and better delivery to the
central nervous system through the
blood brain barrier. For example, engineered glycans, such as
zanamivir and
oseltamivir have been designed to bind to viral
sialidases, which are enzymes that play key roles in
viral replication cycles, such as for
influenza. With these sialidases inhibited,
viral budding and entry into host cells is inhibited. Other drugs, such as
miglitol and
acarbose, serve as therapeutic drugs to people with
Type 2 diabetes, as these engineered glycan derivatives bind to
glucosidases and
amylases to help control patient's
blood sugar level. == See also ==