Abstract
The injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of the Siglec family (sialic-acid binding immunoglobulin-like lectin). In earlier studies, we identified the lead structure 5, which shows a 250-fold improved in vitro affinity for MAG compared to the tetrasaccharide binding epitope of GQ1balpha (1), the best physiological MAG ligand described so far. By modifying the 2- and 5-position, the affinity of 5 could be further improved to the nanomolar range (-->19a). Docking studies to a homology model of MAG allowed the rationalization of the experimental binding properties. Finally, pharmacokinetic parameters (stability in the cerebrospinal fluid, logD and permeation through the BBB) indicate the drug-like properties of the high-affinity antagonist 19a.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Magnetic Resonance Spectroscopy
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Mice
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Models, Molecular*
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Molecular Weight
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Myelin-Associated Glycoprotein / antagonists & inhibitors*
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Myelin-Associated Glycoprotein / chemistry
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N-Acetylneuraminic Acid / analogs & derivatives
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N-Acetylneuraminic Acid / chemical synthesis
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N-Acetylneuraminic Acid / chemistry
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N-Acetylneuraminic Acid / pharmacokinetics
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Protein Binding
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Sialic Acids / chemical synthesis*
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Sialic Acids / chemistry
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Sialic Acids / pharmacokinetics
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Structure-Activity Relationship
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Surface Plasmon Resonance
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Thermodynamics
Substances
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((2,3-difluorobenzyl) 5-fluoroacetamido-9-(4-chlorobenzamido)-3,5,9-trideoxy-d-glycerogalacto-2-nonulopyranosid)onic acid
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Myelin-Associated Glycoprotein
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Recombinant Proteins
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Sialic Acids
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N-Acetylneuraminic Acid