Achieving
selective inhibition of chemokine activity by structurally
well-defined heparan sulfate (HS) or HS mimetic molecules can provide
important insights into their roles in individual physiological and
pathological cellular processes. Here, we report a novel tailor-made
HS mimetic, which furnishes an exclusive iduronic acid (IdoA) scaffold
with different sulfation patterns and oligosaccharide chain lengths
as potential ligands to target chemokines. Notably, highly sulfated-IdoA
tetrasaccharide (I-45) exhibited strong binding to CCL2
chemokine thereby blocking CCL2/CCR2-mediated in vitro cancer cell invasion and metastasis. Taken together, IdoA-based
HS mimetics offer an alternative HS substrate to generate selective
and efficient inhibitors for chemokines and pave the way to a wide
range of new therapeutic applications in cancer biology and immunology.
We report the synthesis of novel HS tetrasaccharides. High throughput screening using glycan microarray and SPR identified the rare HS analog for selectively inhibiting CCL2 mediated cell migration and invasion.
L‐Iduronic acid (IdoA) plays a pivotal role in glycosaminoglycan (GAG) protein interactions. However, the structural microheterogeneity of GAG appears to impede the systematic investigation of IdoA functions. Under such conditions, oligo‐Iduronic acid (Oligo‐IdoA) are ideal and straightforward heparin mimetics to unravel the relationship between IdoA structure and functions. Herein, we report for the first‐time linear synthesis of rare oligo‐IdoA precursor utilizing anhydrous β‐L‐idopyranosyl and IdoA thiophenol building block. After screening various synthetic strategies, we have Installed successive IdoA by 5 step reactions with 25–26 % overall yield. These oligo‐IdoA are expected to be excellent probes to understand conformational plasticity of IdoA and fine tune carbohydrate–protein interactions.
Heparan sulfate glycosaminoglycans provides extracellular matrix defense against heavy metals cytotoxicity. Identifying the precise glycan sequences that bind a particular heavy metal ion is a key for understanding those interactions. Here, electrochemical and surface characterization techniques were used to elucidate the relation between the glycans structural motifs, uronic acid stereochemistry, and sulfation regiochemistry to heavy metal ions binding. A divergent strategy was employed to access a small library of structurally well-defined tetrasaccharides analogs with different sulfation patterns and uronic acid compositions. These tetrasaccharides were electrochemically grafted onto glassy carbon electrodes and their response to heavy metal ions was monitored by electrochemical impedance spectroscopy. Key differences in the binding of Hg(II), Cd(II), and Pb(II) were associated with a combination of the uronic acid type and the sulfation pattern.
Selectins are type-I transmembrane glycoproteins that are ubiquitously expressed on activated platelets, endothelial cells, and leukocytes. They bind to cell surface glycoproteins and extracellular matrix ligands, regulate the rolling of leukocytes in the blood capillaries, and recruit them to inflammatory sites. Hence, they are potential markers for the early detection and inhibition of inflammatory diseases, thrombosis, cardiovascular disorders, and tumor metastasis. Fucosylated and sialylated glycans, such as sialyl Lewisx, its isoform sialyl Lewisa, and heparan sulfate, are primary selectin ligands. Functionalization of these selectin-binding ligands on multivalent probes, such as nanoparticles, liposomes, and polymers, not only inhibits selectin-mediated biological activity but is also involved in direct imaging of the inflammation site. This review briefly summarizes the selectin-mediated various diseases such as thrombosis, cancer and recent progress in the different types of multivalent probes used to target selectins.
We report the discovery of a potential heparan sulfate (HS) ligand to target several growth factors using 13 unique HS tetrasaccharide ligands. By employing an HS microarray and SPR, we...
Recently,
the activity of heparan sulfate (HS) has led to the discovery
of many drug candidates that have the potential to impact both medical
science and human health. However, structural diversity and synthetic
challenges impede the progress of HS research. Here, we report a library
of novel l-iduronic acid (IdoA)-based HS mimics that are
highly tunable in conformation plasticity and sulfation patterns to
produce many of the functions of native HS oligosaccharides. The NMR
analysis of HS mimics confirmed that 4-O-sulfation
enhances the population of the 1C4 geometry.
Interestingly, the 1C4 conformer becomes exclusive
upon additional 2-O-sulfation. HS mimic microarray
binding studies with different growth factors showed that selectivity
and avidity are greatly modulated by the oligosaccharide length, sulfation
code, and IdoA conformation. Particularly, we have identified 4-O-sulfated IdoA disaccharide (I-21) as a potential
ligand for vascular endothelial growth factor (VEGF165),
which in a multivalent display modulated endothelial cell proliferation,
migration, and angiogenesis. Overall, these results encourage the
consideration of HS mimics for therapeutic applications.
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