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Structural Biology and Protein Engineering of Thrombolytics

Název česky Strukturní biologie a proteinové inženýrství trombolytik
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MIČAN Jan TOUL Martin BEDNÁŘ David DAMBORSKÝ Jiří

Rok publikování 2019
Druh Článek v odborném periodiku
Časopis / Zdroj Computational and Structural Biology Journal
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
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Doi http://dx.doi.org/10.1016/j.csbj.2019.06.023
Klíčová slova Fibrinolysis; Staphylokinase; Streptokinase; Thrombolysis; Tissue plasminogen activator; Urokinase
Popis Myocardial infarction and ischemic stroke are the most frequent causes of death or disability worldwide. Due to their ability to dissolve blood clots, the thrombolytics are frequently used for their treatment. Improving the effectiveness of thrombolytics for clinical uses is of great interest. The knowledge of the multiple roles of the endogenous thrombolytics and the fibrinolytic system grows continuously. The effects of thrombolytics on the alteration of the nervous system and the regulation of the cell migration offer promising novel uses for treating neurodegenerative disorders or targeting cancer metastasis. However, secondary activities of thrombolytics may lead to life-threatening side-effects such as intracranial bleeding and neurotoxicity. Here we provide a structural biology perspective on various thrombolytic enzymes and their key properties: (i) effectiveness of clot lysis, (ii) affinity and specificity towards fibrin, (iii) biological half-life, (iv) mechanisms of activation/inhibition, and (v) risks of side effects. This information needs to be carefully considered while establishing protein engineering strategies aiming at the development of novel thrombolytics. Current trends and perspectives are discussed, including the screening for novel enzymes and small molecules, the enhancement of fibrin specificity by protein engineering, the suppression of interactions with native receptors, liposomal encapsulation and targeted release, the application of adjuvants, and the development of improved production systems.
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