Molecular recognition and proteoglycan mimic arrangement: modulating cisplatin toxicity.

We have demonstrated that cisplatin (CP), an anticancer drug, showed a preference for binding the sulfated-L-iduronic acid (S-L-IdoA) unit over the sulfated-D-glucuronic acid unit of heparan sulfate. The multivalency of S-L-IdoA, such as in the proteoglycan mimic, resulted in distinct modes of cell-surface engineering in normal and cancer cells, with these disparities having a significant impact on CP-mediated toxicity.

Synergestic interplay of uronic acid and sulfation composition of heparan sulfate on molecular recognition to activity.

Heparan sulfate (HS) is ubiquitous polysaccharide on the surface of all mammalian cells and extracellular matrices. The incredible structural complexity of HS arises from its sulfation patterns and disaccharide compositions, which orchestrate a wide range of biological activities. Researchers have developed elegant synthetic methods to obtain well-defined HS oligosaccharides to understand the structure-activity relationship. These studies revealed that specific sulfation codes and uronic acid variants could synergistically modulate HS-protein interactions (HSPI). Additionally, the conformational flexibility of l-Iduronic acid, a uronic acid unit has emerged as a critical factor in fine-tuning the microenvironment to modulate HSPI. This review delineates how uronic acid composition in HS modulates protein binding affinity, selectivity, and biological activity. Finally, the significance of sulfated homo-oligo uronic acid as heparin mimics in drug development is also discussed.

Sulfation of Heparan and Chondroitin Sulfate Ligands Enables Cell-Specific Homing of Nanoprobes.

Demystifying the sulfation code of glycosaminoglycans (GAGs) to induce precise homing of nanoparticles in tumor cells or neurons influences the development of a potential drug- or gene-delivery system. However, GAGs, particularly heparan sulfate (HS) and chondroitin sulfate (CS), are structurally highly heterogeneous, and synthesizing well-defined HS/CS composed nanoparticles is challenging. Here, we decipher how specific sulfation patterns on HS and CS regulate receptor-mediated homing of nanoprobes in primary and secondary cells. We discovered that aggressive cancer cells such as MDA-MB-231 displayed a strong uptake of GAG-nanoprobes compared to mild or moderately aggressive cancer cells. However, there was no selectivity towards the GAG sequences, thus indicating the presence of more than one form of receptor-mediated uptake. However, U87 cells, olfactory bulb, and hippocampal primary neurons showed selective or preferential uptake of CS-E-coated nanoprobes compared to other GAG-nanoprobes. Furthermore, mechanistic studies revealed that the 4,6-O-disulfated-CS nanoprobe used the CD44 and caveolin-dependent endocytosis pathway for uptake. These results could lead to new opportunities to use GAG nanoprobes in nanomedicine.

Pairing Nanoparticles Geometry with TLR Agonists to Modulate Immune Responses for Vaccine Development.

Nanotechnology-based vaccine development necessitates understanding the crucial biophysical properties of nanostructures that alter immune responses. In this study, we demonstrate the synergistic effect of gold nanoparticles (AuNPs) shapes with toll-like receptor (TLR) agonists in immune modulation activity. Our results showed that CpG- and imidazoquinoline-conjugated rod-shaped AuNPs display relatively fast uptake by bone marrow-derived macrophage cells but exhibit poor immunogenic responses compared to their spherical and star-shaped AuNP counterparts. Surprisingly, star-shaped AuNPs exhibited intense pro-inflammatory cytokine secretion. Further mechanistic studies showed that star-shaped AuNPs were abundantly localized in the late endosome and lysosomal regions, whereas rod-shaped AuNPs were majorly sequestered in the mitochondrial region. These findings reveal that the shape of the nanostructures plays a pivotal role in driving the adjuvant molecules toward their receptors and altering immune responses.

Profiling Heparan Sulfate-Heavy Metal Ions Interaction Using Electrochemical Techniques.

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.

Continuous-Flow Accelerated Sulfation of Heparan Sulfate Intermediates.

We report for the first time a continuous-flow strategy to execute O-sulfation modification of heparan sulfate (HS) oligosaccharides. A systematic investigation of the influence of the flow parameters on the installation of the sulfate group on glucosamine monosaccharide can aid the development of a comprehensive, quick, and reliable strategy for O-sulfation of HS oligosaccharide precursors. Deprotection of the sulfated heparin intermediates led to the development of a comprehensive biologically inspired oligosaccharide library to understand the crucial structure-function relationship of HS.

Demystifying a hexuronic acid ligand that recognizes Toxoplasma gondii and blocks its invasion into host cells.

Toxoplasma gondii is a ubiquitous eukaryotic pathogen responsible for toxoplasmosis in humans and animals. This parasite is an obligate intracellular pathogen and actively invades susceptible host cells, a process which is mediated by specific receptor-ligand interactions. Here, we have identified an unnatural 2,4-disulfated d-glucuronic acid (Di-S-GlcA), a hexuronic acid composed of heparin/heparan sulfate, as a potential carbohydrate ligand that can selectively bind to T. gondii parasites. More importantly, the gelatin conjugated Di-S-GlcA multivalent probe displayed strong inhibition of parasite entry into host cells. These results open perspective for the future use of Di-S-GlcA epitopes in biomedical applications against toxoplasmosis.