Tailored chondroitin sulfate glycomimetics via a tunable multivalent scaffold for potentiating NGF/TrkA-induced neurogenesis

Abstract

We have engineered structurally well-defined tunable chondroitin sulfate glycopeptides using a polyproline scaffold to selectively modulate the NGF-mediated neuronal signaling pathway.

Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns

“…Fourth, PGMs generate sulfation patterns in a continuous fashion along their backbone axis. This relates better to GAGs than our previous attempt 12 and the typical GAG mimetic paradigm of introducing short GAG sequences as pendant groups around a non-saccharide backbone. 34 , 35 …”

“…Specifically, we created GAG mimetics with CS-E disaccharides as bioactive sulfate-bearing motifs and polyprolines as non-carbohydrate backbones that aimed to recover the characteristic of spatial tunability. 12 Despite successes in producing GAG mimetics that could potentiate NGF/TrkA-induced neurogenesis, the challenge remains apparent. Arduous saccharide synthesis, while reduced, is still needed to a certain degree to create GAG-appropriate sulfate-bearing motifs.…”

Fluorous-tag assisted synthesis of a glycosaminoglycan mimetic tetrasaccharide as a high-affinity FGF-2 and midkine ligand

“…14 For instance, different types of multivalent scaffolds displaying short and easily prepared GAG oligomers have been proposed as promising GAG mimetics. [15][16][17][18][19][20][21] These multivalent systems include dendrimers and polymers functionalized with CS and heparin oligosaccharide sequences. Sulfated non-GAG oligosaccharides, such as mannose derivatives PI-88 and PG545, have also been reported as GAG mimetics with potent anticancer activity and high binding affinities to angiogenic growth factors.…”

Synthesis of Fucosylated Chondroitin Sulfate Glycoclusters: A Robust Route to New Anticoagulant Agents

“…The "cluster effect" is known to enhancet he interaction between carbohydrates and proteins, [23] and previouss tudies have shownt hat synthetic glycopolymers or clusters could mimic the activity of natural GAGs in neurite outgrowth, [24] anticoagulant action, [25] and inhibition of Alzheimer's disease protease BACE-1. [26] More importantly,aseries of glycoclusters with different valences, orientations, and molecular weights are readily accessible simply through adjustment of the frameworks, which makes it easy to summarize structure-activity relationships and guide effort to prepareb etter targets.A sf or FuCS, we expect to know how many trisaccharide repeating units are necessary for potent activity andw hether the sulfation patterns influencei ts anticoagulantb ehavior,a nd then screen as tructurally defined minimal active fragment through glycocluster assembly.…”