Human plasmin enzymatic activity is inhibited by chemically modified dextrans

Area of Science:

• Biochemistry
• Biomaterials Science
• Pharmacology

Background:

• Synthetic dextran derivatives mimic heparin/heparan sulfate, promoting tissue repair.
• These compounds protect growth factors and inhibit neutrophil elastase in vitro.
• The study investigates dextran derivatives' capacity to inhibit human plasmin activity.

Purpose of the Study:

• To evaluate the inhibitory effects of novel dextran derivatives on human plasmin.
• To characterize the binding kinetics and mechanism of inhibition by the most effective dextran derivative.
• To explore the potential of these dextran derivatives in regulating plasmin-mediated processes.

Main Methods:

• In vitro enzymatic assays to measure plasmin amidolytic activity inhibition.
• Optical biosensor analysis to determine binding affinity (K(d)) and kinetics.
• Competitive binding experiments using known plasmin inhibitors and fragments.
• Assessment of RG1192's effect on plasminogen activation and substrate proteolysis.

Main Results:

• Dextran derivative RG1192, containing carboxymethyl, sulfate, and benzylamide groups, demonstrated potent inhibition of plasmin.
• RG1192 exhibited tight-binding, hyperbolic noncompetitive inhibition with a K(i) of 2.8 x 10(-8) M.
• RG1192 bound plasminogen with high affinity (K(d) = 3 x 10(-8) M) at the lysine-binding sites.
• RG1192 inhibited plasminogen activation and plasmin-mediated degradation of fibronectin and laminin.

Conclusions:

• Specific dextran derivatives, particularly RG1192, can effectively regulate plasmin activity.
• RG1192 acts by inhibiting plasmin's catalytic function and impeding plasminogen generation.
• These findings suggest potential therapeutic applications for dextran derivatives in managing processes involving plasmin.