Low molecular weight antagonists of the myelin-associated glycoprotein: synthesis, docking, and biological evaluation.
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.
Mesch
Stefanie
S
Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
Moser
Delia
D
Strasser
Daniel S
DS
Kelm
Antje
A
Cutting
Brian
B
Rossato
Gianluca
G
Vedani
Angelo
A
Koliwer-Brandl
Hendrik
H
Wittwer
Matthias
M
Rabbani
Said
S
Schwardt
Oliver
O
Kelm
Soerge
S
Ernst
Beat
B
D000818:Animals; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008970:Molecular Weight; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D012794:Sialic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
C547949:((2,3-difluorobenzyl) 5-fluoroacetamido-9-(4-chlorobenzamido)-3,5,9-trideoxy-d-glycerogalacto-2-nonulopyranosid)onic acid; D018992:Myelin-Associated Glycoprotein; D011994:Recombinant Proteins; D012794:Sialic Acids; D019158:N-Acetylneuraminic Acid