Role of Fibrinolytic Enzymes in Anti-Thrombosis Therapy

Abstract

Thrombosis, a major cause of deaths in this modern era responsible for 31% of all global deaths reported by WHO in 2017, is due to the aggregation of fibrin in blood vessels which leads to myocardial infarction or other cardiovascular diseases (CVDs). Classical agents such as anti-platelet, anti-coagulant drugs or other enzymes used for thrombosis treatment at present could leads to unwanted side effects including bleeding complication, hemorrhage and allergy. Furthermore, their high cost is a burden for patients, especially for those from low and middle-income countries. Hence, there is an urgent need to develop novel and low-cost drugs for thrombosis treatment. Fibrinolytic enzymes, including plasmin like proteins such as proteases, nattokinase, and lumbrokinase, as well as plasminogen activators such as urokinase plasminogen activator, and tissue-type plasminogen activator, could eliminate thrombi with high efficacy rate and do not have significant drawbacks by directly degrading the fibrin. Furthermore, they could be produced with high-yield and in a cost-effective manner from microorganisms as well as other sources. Hence, they have been considered as potential compounds for thrombosis therapy. Herein, we will discuss about natural mechanism of fibrinolysis and thrombus formation, the production of fibrinolytic enzymes from different sources and their application as drugs for thrombosis therapy.

Keywords: fibrinolytic enzymes; plasminogen activators; proteases; thrombolytic drugs; thrombosis therapy.

FIGURE 1

Domain structure of streptokinase. Streptokinase consists of three domains: α domain at 1–146, β domain at 147–290, and γ domain at 291–414 of the amino acid positions. It also contains many functional regions across the domain such as Asp41–His48 region between the first to 59th 59 amino acid residues of α domain, Lys256, Lys257, and Val158–Arg219 region of β domain, as well as Leu314–Ala342 region of γ domain.

FIGURE 2

Domain structure of staphylokinase consisting two domains of equal size.

FIGURE 3

Domain structure of nattokinase consisting of a single polypeptide chain.

FIGURE 4

Structure of urokinase-type plasminogen activator (uPA). Pro-uPA is secreted as an inactive single polypeptide chain consisting of a growth factor domain, kringle domain and serine protease domain, and undergoes first proteolytic cleavage between its Lys158 and IIe159. A second-round cleavage at the peptide bond between its Lys135 and Lys 136 totally cleaves the two chains of uPA into two parts: the inactive amino-terminal fragment (ATF) and active low molecular weight form of uPA (Mahmood et al., 2018).

FIGURE 5

Domain structure of recombinant tissue-type plasminogen activator (rtPA). It consists of fibronectin type I domain, an epidermal growth factor domain, as well as kringle 1, kringle 2 and serine protease domains.

FIGURE 6

Schematic diagram showing the mechanism of action of thrombolytic drugs.