Potent, Selective, Allosteric Inhibition of Human Plasmin by Sulfated Non-Saccharide Glycosaminoglycan Mimetics

Although
plasmin inhibitors could be used in multiple disorders,
their use has been restricted to preventing blood loss in hemostatic
dysregulation because of poor efficacy and adverse effects of current
agents. We reasoned that a new class of direct inhibitors that offer
better efficacy, selectivity, and safety could be discovered by exploiting
allosterism in plasmin, a protease homologous to other allosteric
serine proteases. We report on the synthesis, biological activity,
and mechanism of action of a group of small molecules, called non-saccharide
glycosaminoglycan mimetics (NSGMs), as direct allosteric plasmin inhibitors.
Our results show that distinct NSGMs selectively inhibit human full-length
plasmin. The molecule inhibited clot lysis, alluding to its promise
as an allosteric regulator of plasmin. We show that direct allosteric
inhibition of plasmin could led to new antifibrinolytic agent(s) that
may exhibit better efficacy, potency, selectivity, and safety in comparison
to current therapy.