Heparan sulfate glycomimetics<i>via</i>iterative assembly of “clickable” disaccharides

Heparan sulfate (HS) contains variably repeating disaccharide units organized into high-and lowsulfated domains. This rich structural diversity enables HS to interact with many proteins and regulate key signaling pathways. Efforts to understand structurefunction relationships and harness the therapeutic potential of HS are hindered by the inability to synthesize an extensive library of well-defined HS structures. We herein report a rational and expedient approach to access a library of 27 oligosaccharides from natural aminoglycosides as HS mimetics in 7-12 steps. This strategy significantly reduces the number of steps as compared to the traditional synthesis of HS oligosaccharides from monosaccharide building blocks. Combined with computational insight, we identify a new class of four trisaccharide compounds derived from the aminoglycoside tobramycin that mimic natural HS and have a strong binding to heparanase but a low affinity for off-target platelet factor-4 protein.

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Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies

Wakpal

Pathiranage

Walker

et al. 2023

Angewandte Chemie

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show abstract

Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies

et al. 2023

View full text Add to dashboard Cite

Heparan sulfate (HS) contains variably repeating disaccharide units organized into high‐ and low‐sulfated domains. This rich structural diversity enables HS to interact with many proteins and regulate key signaling pathways. Efforts to understand structure‐function relationships and harness the therapeutic potential of HS are hindered by the inability to synthesize an extensive library of well‐defined HS structures. We herein report a rational and expedient approach to access a library of 27 oligosaccharides from natural aminoglycosides as HS mimetics in 7–12 steps. This strategy significantly reduces the number of steps as compared to the traditional synthesis of HS oligosaccharides from monosaccharide building blocks. Combined with computational insight, we identify a new class of four trisaccharide compounds derived from the aminoglycoside tobramycin that mimic natural HS and have a strong binding to heparanase but a low affinity for off‐target platelet factor‐4 protein.

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Synthesis and interaction with growth factors of sulfated oligosaccharides containing an anomeric fluorinated tail

de Paz,

García-Jiménez,

Jafari

et al. 2023

Bioorganic Chemistry

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Heparan sulfate glycomimeticsviaiterative assembly of “clickable” disaccharides

Abstract: Heparan sulfate (HS) glycosaminoglycans are widely expressed on the mammalian cell surfaces and extracellular matrices and play important roles in variety of cell functions. Studies on the structure-activity relationships of...

Cited by 5 publications

References 61 publications

Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies

Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies

Rational Design and Expedient Synthesis of Heparan Sulfate Mimetics from Natural Aminoglycosides for Structure and Activity Relationship Studies

Synthesis and interaction with growth factors of sulfated oligosaccharides containing an anomeric fluorinated tail

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