47
immune response, contributing severe allergic reactions and life-threatening conditions. Covalent modification of enzymes by molecules such as polyethylene glycol
is used to circumvent the immunogenicity. Another problem associated with
enzymes in therapeutics is their relatively short half-life. Microencapsulation and
artificial liposomal entrapment are some of the techniques used to increment the
stability and half-life of enzyme drugs. Finally the purity of enzymes used for therapy is also a significant factor. This in turn makes enzyme drugs more expensive.
However, advancements in drug development and delivery over the past few
decades have revolutionized enzyme therapy. Newer drugs with improved stability
and less antigenicity have been developed.
2.2
Enzymes for Treatment of Cardiovascular Diseases
Fibrin is a major protein formed during wound healing and is the end product of the
blood clotting cascade. It prevents loss of blood during injuries. Enzymes like plasmin directly degrade fibrin. A balance between fibrin formation and removal is
required for normal functioning of the system. However, when the balance shifts
towards the improper accumulation of fibrin, thrombolytic diseases such as acute
myocardial infarction and stroke occur. Thirty-one per cent of mortality worldwide
in 2012 was due to cardiovascular diseases according to the World Health
Organization.
Elimination of blood clot or thrombus is the key factor in thrombolytic therapy.
Either of the therapeutic approaches, treatment with anti-coagulants (warfarin and
heparin) or antiplatelets (dipyridamole and aspirin), or surgical treatment of thrombus or fibrinolytic enzyme therapy can be practised to remove or lyse the clot.
Thrombolytic therapy using fibrinolytic enzyme has an advantage over anticoagulants and antiplatelets, as the enzymes could act upon the existing clot.
Thrombolytic enzymes are thus known as clot buster enzymes. Based on the mechanism of action they are of two types, viz. plasminogen activators (e.g. tissue-type
plasminogen activator (tPA) and urokinase) and plasmin-like enzymes (e.g. nattokinase and lumbrokinase).
2.2.1 Plasminogen Activators
2.2.1.1 Tissue-Type Plasminogen Activator (tPA)
Tissue plasminogen activator (tPA) is a serine protease enzyme which converts plasminogen to plasmin and thus aids in clot dissolution. Tissue plasminogen activator
consists of 527 amino acids with a molecular weight of 70 KDa (Pennica et al.
1983). Normally they are found in endothelial cells and assist in restoring the blood
flow after thrombus is formed. Under certain physiological conditions fibrinolysis
may not occur because plasminogen activators as well as plasmin are inhibited by
circulating plasminogen activator inhibitors and α2 plasmin inhibitors. However,
2 Therapeutic Enzymes
immune response, contributing severe allergic reactions and life-threatening conditions. Covalent modification of enzymes by molecules such as polyethylene glycol
is used to circumvent the immunogenicity. Another problem associated with
enzymes in therapeutics is their relatively short half-life. Microencapsulation and
artificial liposomal entrapment are some of the techniques used to increment the
stability and half-life of enzyme drugs. Finally the purity of enzymes used for therapy is also a significant factor. This in turn makes enzyme drugs more expensive.
However, advancements in drug development and delivery over the past few
decades have revolutionized enzyme therapy. Newer drugs with improved stability
and less antigenicity have been developed.
2.2
Enzymes for Treatment of Cardiovascular Diseases
Fibrin is a major protein formed during wound healing and is the end product of the
blood clotting cascade. It prevents loss of blood during injuries. Enzymes like plasmin directly degrade fibrin. A balance between fibrin formation and removal is
required for normal functioning of the system. However, when the balance shifts
towards the improper accumulation of fibrin, thrombolytic diseases such as acute
myocardial infarction and stroke occur. Thirty-one per cent of mortality worldwide
in 2012 was due to cardiovascular diseases according to the World Health
Organization.
Elimination of blood clot or thrombus is the key factor in thrombolytic therapy.
Either of the therapeutic approaches, treatment with anti-coagulants (warfarin and
heparin) or antiplatelets (dipyridamole and aspirin), or surgical treatment of thrombus or fibrinolytic enzyme therapy can be practised to remove or lyse the clot.
Thrombolytic therapy using fibrinolytic enzyme has an advantage over anticoagulants and antiplatelets, as the enzymes could act upon the existing clot.
Thrombolytic enzymes are thus known as clot buster enzymes. Based on the mechanism of action they are of two types, viz. plasminogen activators (e.g. tissue-type
plasminogen activator (tPA) and urokinase) and plasmin-like enzymes (e.g. nattokinase and lumbrokinase).
2.2.1 Plasminogen Activators
2.2.1.1 Tissue-Type Plasminogen Activator (tPA)
Tissue plasminogen activator (tPA) is a serine protease enzyme which converts plasminogen to plasmin and thus aids in clot dissolution. Tissue plasminogen activator
consists of 527 amino acids with a molecular weight of 70 KDa (Pennica et al.
1983). Normally they are found in endothelial cells and assist in restoring the blood
flow after thrombus is formed. Under certain physiological conditions fibrinolysis
may not occur because plasminogen activators as well as plasmin are inhibited by
circulating plasminogen activator inhibitors and α2 plasmin inhibitors. However,
2 Therapeutic Enzymes