Assessment through chemical synthesis of the size of the heparin sequence involved in thrombin inhibition.
Deca- to eicosasaccharides having the generic structure methyl(sodium 2,3-di-O-methyl-4-O-sodium sulfonato-alpha-L-idopyranosyluronate)-(1-->4)-[(2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranosyl)-(1-->4)-(sodium 2,3-di-O-methyl-alpha-L-idopyranosyluronate)-(1-->4)]n-2,3,6-tri-O-sodiu m sulfonato-alpha-D-glucopyranoside have been synthesized from a single disaccharide precursor. All of them bind to and activate antithrombin. When n < or = 6 only Factor Xa inhibition is observed, whereas when n > 6 Factor Xa and thrombin are both inhibited in the presence of antithrombin. These results indicate that, in heparin, the sequence involved in antithrombin-catalyzed thrombin inhibition is a pentadeca- or a hexadecasaccharide.
Duchaussoy
P
P
Sanofi Recherche, Haemobiology Research Department, Toulouse, France.
Jaurand
G
G
Driguez
P A
PA
Lederman
I
I
Ceccato
M L
ML
Gourvenec
F
F
Strassel
J M
JM
Sizun
P
P
Petitou
M
M
Herbert
J M
JM
D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006493:Heparin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009904:Optical Rotation; D013917:Thrombin / Q000037:antagonists & inhibitors*
D004187:Disaccharides; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007202:Indicators and Reagents; D009844:Oligosaccharides; D006493:Heparin; D013917:Thrombin