Uncharged P-selectin blockers.
The blocking potency of P- and L-selectin was studied for certain small molecule mannosides and their polyacrylamide (PAA, 30 kDa) conjugates in comparison to SiaLe(x) and fucoidan. Two experimental systems were used: (1) solid phase static assay based on recombinant selectins, and (2) P-selectin dependent rat peritoneal inflammation. betaMan-SC6H4NO2- p was four times more potent P-selectin inhibitor as compared to SiaLe(x). Docking of this molecule onto the P-selectin carbohydrate-binding site demonstrated that a nitro group enabled an electrostatic interaction with residue Lys 84, while the phenyl ring and the CH2 at C-6 contacted the CH2 groups of the same Lys residue. In vivo, betaMan-SC6H4NO2- p blocked experimental inflammation better than SiaLe(x), but significantly lower than fucoidan. In vitro Man-polyacrylic acid conjugates appeared to be very potent inhibitors comparable to fucoidan, uncharged Man-PAA proved rather active, comparable to SiaLe(x)-PAA both in vitro, and in vivo, whereas mannan did not display any P-selectin blocking effect.
Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
T V
TV
Pochechueva
O E
OE
Galanina
N A
NA
Ushakova
M E
ME
Preobrazhenskaya
M A
MA
Sablina
N E
NE
Nifantiev
Yu V
YV
Tsvetkov
Ya V
YV
Vozney
A
A
Imberty
N V
NV
Bovin
D000180:Acrylic Resins / Q000378:metabolism*; D000818:Animals; D006001:Glycoconjugates / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism; D008362:Mannosides / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D051381:Rats; D000099166:Polyacrylamides
D000180:Acrylic Resins; D006001:Glycoconjugates; D019041:L-Selectin; D008362:Mannosides; D019007:P-Selectin; D011134:Polysaccharides; D000099166:Polyacrylamides; C007789:fucoidan