Fibrinolysis Inhibitors: Potential Drugs for the Treatment and Prevention of Bleeding

Abstract

Hyperfibrinolytic situations can lead to lifethreatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, εaminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crystal structures of the main antifibrinolytic targets, the lysine binding sites on plasminogen's kringle domains, and plasmin's serine protease domain greatly contributed to the structure-based drug design of novel inhibitor classes. Two series of ligands targeting the lysine binding sites have been recently described, which are more potent than the most-widely used antifibrinolytic agent, tranexamic acid. Furthermore, four types of promising active site inhibitors of plasmin have been developed: tranexamic acid conjugates targeting the S1 pocket and primed sites, substrate-analogue linear homopiperidylalanine-containing 4amidinobenzylamide derivatives, macrocyclic inhibitors addressing nonprimed binding regions, and bicyclic 14-mer SFTI-1 analogues blocking both, primed and nonprimed binding sites of plasmin. Furthermore, several allosteric plasmin inhibitors based on heparin mimetics have been developed.

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

“…In search for suitable antiviral therapies against SARS-CoV-2 infections, protease inhibitors that have been approved for other applications may be promising for drug repurposing to treat COVID-19. Aprotinin is a broad range serine protease inhibitor isolated from bovine lung, used as a fibrinolysis inhibitor to reduce perioperative bleeding (reviewed in reference 44 ) and has long been known to inhibit influenza A virus activation and replication in cell culture and in mice in vivo ( 30 ). In a clinical trial, inhalation of aerosolized aprotinin in patients with influenza and parainfluenza markedly reduced the duration of symptoms without causing side effects ( 30 ).…”

TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

“…In search for suitable antiviral therapies against SARS-CoV-2 infections, protease inhibitors that have been approved for other applications may be promising for drug repurposing to treat COVID-19. Aprotinin is a broad range serine protease inhibitor isolated from bovine lung, which is used as a fibrinolysis inhibitor to reduce perioperative bleeding (reviewed in Steinmetzer et al, 2020) and has long been known to inhibit influenza A virus activation and replication in cell culture and in mice in vivo (Zhirnov et al, 2011). In a clinical trial, inhalation of aerosolized aprotinin in patients with influenza and parainfluenza markedly reduced the duration of symptoms without causing side effects (Zhirnov et al, 2011).…”

Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid

“…The dual inhibition of Plm and FXa was shown for 40 (Ki = 8.4 and 0.0003 μM for Plm and FXa, respectively) [37,38]. Based on the structure of 40, the development of orally bioavailable FXIa inhibitors (41,42) is progressing at BMS [39,40] (Figure 3). Bayer AG investigated other analogues of Plm inhibitors containing both TXA and side-chain extended Phe residues.…”

“…For example, compound 43 elongated at the para position of Phe and at the C-terminal heterocycle moiety and exhibited dual inhibition (IC50 = 0.32 and 3.5 nM for Plm and FXIa, respectively) [41] (Figure 4). Steinmetzer et al discussed the similar molecular alteration in their review [42]. Bayer AG derivatives are currently being evaluated for their pharmacokinetics and pharmacodynamics properties, and for safety for eventual application in antithrombotic therapy.…”