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.
Keywords: Cardiovascular thrombosis, chemical modification, chimeric streptokinase, fibrinolysis, heterogenicity,
PEGylation, plasminogen activator, protein engineering, SK, specific activity, structure modelling, thrombolytic agent.
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