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Published on: August 20, 2014
Antithrombin activation by nonsulfated, non-polysaccharide organic polymer
Bernhard H Monien1, Umesh R Desai
1Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
Journal of Medicinal Chemistry
|February 18, 2005
Summary
Researchers discovered that carboxylate-based molecules, like poly(acrylic acid), can activate antithrombin, accelerating the inhibition of blood-clotting enzymes. This finding opens possibilities for developing new, orally available antithrombin activators without using sulfates.
Area of Science:
- Biochemistry
- Pharmacology
- Polymer Chemistry
Background:
- Antithrombin's anticoagulant activity is crucial for regulating blood coagulation.
- Polysulfated polysaccharides are the only known activators of antithrombin, limiting therapeutic options.
Purpose of the Study:
- To investigate if nonsulfated molecules containing carboxylic acid groups can activate antithrombin.
- To demonstrate the potential for developing novel antithrombin activators.
Main Methods:
- Synthesis and characterization of linear poly(acrylic acid)s.
- Binding assays to confirm poly(acrylic acid) interaction with antithrombin.
- Enzyme inhibition assays measuring the acceleration of factor Xa and thrombin inhibition by antithrombin.
Main Results:
- Linear poly(acrylic acid)s were shown to bind effectively to antithrombin.
- Poly(acrylic acid)s significantly accelerated the inhibition of both factor Xa and thrombin by antithrombin.
- The observed activation occurred in the absence of any sulfate groups.
Conclusions:
- Nonsulfated molecules, specifically those with carboxylic acid groups, can function as potent antithrombin activators.
- This research validates the principle of carboxylate-based antithrombin activation.
- The findings suggest a potential pathway for developing orally bioavailable antithrombin activators, offering a new therapeutic strategy.
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