Towards A Superior Streptokinase for Fibrinolytic Therapy of Vascular Thrombosis

Abstract

Medical intervention with fibrinolytic drugs such as tissue plasminogen activator (tPA) and streptokinase (SK) is the principal treatment for life-treating thromboembolic disorders. Contrary to tPA, SK is a heterogenic and non-human (bacterial) protein produced by streptococci and its medical application may elicit sever immune and anaphylactic responses that restrict its utilization. Besides, human plasminogen (HPG) activation by SK is not blood-clot specific and associated with a risk of hemorrhage. Despite these limitations, comparative clinical trials on various thrombolytic agents suggested that SK is the most cost-effective fibrinolytic drug and almost as safe as its other counterparts such as tPA. Therefore, a number of studies were conducted to provide structurally modified SK with reduced immunogenicity, higher blood-clot specificity and half-lives. Although there are extensive overlaps in SK structural domains responsible for functionality, immunogenicity and stability that may limit its modifications, various strategies such as genetic manipulations (amino acid substitution /addition /deletion or domain fusions through production of chimeric SK proteins linked to HPG or hirudin) and chemical modification such as (homogenous/site-specific) PEGylation have been employed to develop a superior SK. In addition, data of the latest studies on SK screened from different streptococcal sources indicated the possibility of retrieving naturally occurring SKs with higher activities, less antigenicity and/or more fibrinspecificity. In the present review, after a survey on structure function relationships of SK domains and different strategies for SK improvement, recent advances and potential application of computer and matrix-based analyses for design and introduction of superior SKs will be presented.

Nonsurgical therapy for hydrocephalus: a comprehensive and critical review

“…Urokinase (or urokinase-type plasminogen activator/uPA) is a proteolytic enzyme present in urine, blood, and extracellular matrix; it is also capable of activating plasminogen and it can digest extracellular matrix proteins [ 107 ]. Streptokinase is a bacterial enzyme capable of cleaving plasminogen, although it is less discriminate and can activate plasminogen that is not associated with blood clots [ 108 ]. Thrombolytic therapies for ischemic stroke were first pursued in the 1970s; intravascular recombinant tPA is an important intervention for some adults with early ischemic stroke [ 109 ].…”

PEGylation of Truncated Streptokinase Leads to Formulation of a Useful Drug with Ameliorated Attributes

“…However, if some of its major drawbacks can be rectified, it has the potential to occupy centre-stage as an effective thrombolytic, especially for ischemic strokes. Some drawbacks which invite attention are systemic activation of HPG [ 48 ] and the consequent fibrinogen depletion by SK, which, if rectified, it can be given as a bolus shot instead of a slow infusion that requires hospital settings; another objective has been to reduce SK’s antigenicity as much as possible, while increasing its in vivo half-life. It has been earlier shown that PEGylation of SK considerably enhances its therapeutic attributes [ 30 , 49 ] but an uncontrolled (non-specific) PEGylation is likely to lead to non-homogenous populations of PEGylated-SK adducts with varying physiochemical, pharmaceutical and biological properties [ 30 ].…”

Antithrombotic Drugs (Anticoagulants, Antiplatelets, and Thrombolytics)

“…Medical intervention with fibrinolytic drugs such as tissue plasminogen activator and streptokinase is the principal treatment for life-treating thromboembolic disorders [178,179].…”