Antithrombin activation by nonsulfated, non-polysaccharide organic polymer.
Accelerated antithrombin inhibition of procoagulant enzymes has been exclusively achieved with polysulfated polysaccharides. We reasoned that antithrombin activation should be possible with nonsulfated activators based only on carboxylic acid groups. As a proof of the principle, linear poly(acrylic acid)s were found to bind to antithrombin and accelerate inhibition of factor Xa and thrombin. Our work demonstrates that molecules completely devoid of sulfate groups can activate antithrombin effectively and, more importantly, suggests that it may be possible to develop orally bioavailable, carboxylate-based antithrombin activators.
Monien
Bernhard H
BH
Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
Desai
Umesh R
UR
D000180:Acrylic Resins / Q000737:chemistry*; D000991:Antithrombins / Q000819:agonists* / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry
D000180:Acrylic Resins; D000991:Antithrombins; D065427:Factor Xa Inhibitors; C006903:carbopol 940; D013917:Thrombin; D015951:Factor Xa