Recent Advances on Plasmin Inhibitors for the Treatment of Fibrinolysis‐Related Disorders

Abstract

Growing evidence suggests that plasmin is involved in a number of physiological processes in addition to its key role in fibrin cleavage. Plasmin inhibition is critical in preventing adverse consequences arising from plasmin overactivity, e.g., blood loss that may follow cardiac surgery. Aprotinin was widely used as an antifibrinolytic drug before its discontinuation in 2008. Tranexamic acid and ε-aminocaproic acid, two small molecule plasmin inhibitors, are currently used in the clinic. Several molecules have been designed utilizing covalent, but reversible, chemistry relying on reactive cyclohexanones, nitrile warheads, and reactive aldehyde peptidomimetics. Other major classes of plasmin inhibitors include the cyclic peptidomimetics and polypeptides of the Kunitz and Kazal-type. Allosteric inhibitors of plasmin have also been designed including small molecule lysine analogs that bind to plasmin's kringle domain(s) and sulfated glycosaminoglycan mimetics that bind to plasmin's catalytic domain. Plasmin inhibitors have also been explored for resolving other disease states including cell metastasis, cell proliferation, angiogenesis, and embryo implantation. This review highlights functional and structural aspects of plasmin inhibitors with the goal of advancing their design.

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

“…Plasmin, a trypsin-like serine protease, promotes intravascular dissolution of fibrin clots [1,2]. Plasmin inhibitors are clinically used as antifibrinolytics so as to reduce excessive blood loss during major surgeries such as cardiac surgery with cardiopulmonary bypass [3,4].…”

“…Plasmin can also be produced at the cell surface as to contribute to the degradation of extracellular matrix resulting in modulation of tissue remodeling, cell invasion, and/or metastasis and chemotaxis. This implies that inhibitors of plasmin could potentially benefit many other pathologies too including angioedema, chronic inflammatory responses, and lymphoid malignancies [1,2].…”

“…Tranexamic acid and ε-aminocaproic acid, two analogs of lysine, bind to the lysine-binding sites in the kringle domains of plasminogen resulting in attenuation of plasmin formation [1]. Both lysine analogs have no direct inhibitory effect on active plasmin leading to their limited efficacy.…”

“…Several small molecules are being developed as inhibitors of human plasmin [1]. Each of these is an active site inhibitor, which is typically easier to discover considering the availability of known substrate sequence specificity.…”

The isolated human umbilical vein as a bioassay for kinin-generating proteases: An in vitro model for therapeutic angioedema agents

“…This spectrum of susceptibility to inhibitors is well known for KLK-1 [24], however the cell impermeant peptide was not toxic to tissues, as opposed to pefabloc SC. Tranexamic acid at the used concentration inhibits both tPA and plasmin [29], proteases that possess kringle domains and that are upstream of the contact system vs. the generation of BK (Fig. 8).…”