Effects of sulfation on antithrombin-thrombin/factor Xa interactions in semisynthetic low molecular weight heparins

Most of the biological effects of heparin and low molecular weight (LMW) he parins arc related to their ability to bind to many different proteins. To gain insight into structure- activity relationships, we investigated quanti tatively the interactions of a series of sulfated LMW heparins of similar m olecular weights (derived from statistical desulfation of a supersulfated h eparin) with the target enzymes human antithrombin (AT) and thrombin (T). I n addition, we analyzed the activation of the protease inhibitor against T and factor Xa (FXa). A nonlinear correlation between the strength of the AT -heparin complex and the degree of sulfation of the LMW heparins was observ ed, whereas only a modest modulation of T binding to heparin occurred. The efficiency of the heparin derivatives in activating AT toward the proteases is generally high for derivatives exhibiting a low dissociation constant. Only the supersulfated LMW heparin showed serpin activation ability higher than expected from the affinity studies. These results indicate that chemic al modification of the sulfation pattern of LMW heparin can be used to effi ciently modulate binding affinity and activity toward biological targets.