Inhibition of PrPSc formation by synthetic O-sulfated glycopyranosides and their polymers.
Sulfated glycosaminoglycans (GAGs) and sulfated glycans inhibit formation of the abnormal isoform of prion protein (PrPSc) in prion-infected cells and prolong the incubation time of scrapie-infected animals. Sulfation of GAGs is not tightly regulated and possible sites of sulfation are randomly modified, which complicates elucidation of the fundamental structures of GAGs that mediate the inhibition of PrPSc formation. To address the structure-activity relationship of GAGs in the inhibition of PrPSc formation, we screened the ability of various regioselectively O-sulfated glycopyranosides to inhibit PrPSc formation in prion-infected cells. Among the glycopyranosides and their polymers examined, monomeric 4-sulfo-N-acetyl-glucosamine (4SGN), and two glycopolymers, poly-4SGN and poly-6-sulfo-N-acetyl-glucosamine (poly-6SGN), inhibited PrPSc formation with 50% effective doses below 20 microg/ml, and their inhibitory effect became more evident with consecutive treatments. Structural comparisons suggested that a combination of an N-acetyl group at C-2 and an O-sulfate group at either O-4 or O-6 on glucopyranoside might be involved in the inhibition of PrPSc formation. Furthermore, polymeric but not monomeric 6SGN inhibited PrPSc formation, suggesting the importance of a polyvalent configuration in its effect. These results indicate that the synthetic sulfated glycosides are useful not only for the analysis of structure-activity relationship of GAGs but also for the development of therapeutics for prion diseases.
Yamaguchi
Satoko
S
Department of Veterinary Public Health, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro 080-8555, Japan.
Nishida
Yoshihiro
Y
Sasaki
Kenji
K
Kambara
Mikie
M
Kim
Chan-Lan
CL
Ishiguro
Naotaka
N
Nagatsuka
Takehiro
T
Uzawa
Hirotaka
H
Horiuchi
Motohiro
M
D000117:Acetylglucosamine / Q000737:chemistry; D000818:Animals; D002241:Carbohydrates / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008956:Models, Chemical; D011108:Polymers / Q000737:chemistry*; D018620:PrPSc Proteins / Q000737:chemistry* / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy; D011328:Prions; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry
D002241:Carbohydrates; D011108:Polymers; D018620:PrPSc Proteins; D011328:Prions; D013455:Sulfur; D000117:Acetylglucosamine