Structural Biology and Protein Engineering of Thrombolytics

MIČAN, Jan, Martin TOUL, David BEDNÁŘ and Jiří DAMBORSKÝ. Structural Biology and Protein Engineering of Thrombolytics. Computational and Structural Biology Journal. Amsterdam: Elsevier, 2019, vol. 17, No 2019, p. 917-938. ISSN 2001-0370. Available from: https://dx.doi.org/10.1016/j.csbj.2019.06.023.

Basic information

• Original name: Structural Biology and Protein Engineering of Thrombolytics
• Name in Czech: Strukturní biologie a proteinové inženýrství trombolytik
• Authors: MIČAN, Jan (203 Czech Republic, belonging to the institution), Martin TOUL (203 Czech Republic, belonging to the institution), David BEDNÁŘ (203 Czech Republic, guarantor, belonging to the institution) and Jiří DAMBORSKÝ (203 Czech Republic, belonging to the institution).
• Edition: Computational and Structural Biology Journal, Amsterdam, Elsevier, 2019, 2001-0370.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10608 Biochemistry and molecular biology
• Country of publisher: Netherlands
• Confidentiality degree: is not subject to a state or trade secret
• WWW: Full Text
• Impact factor: Impact factor: 6.018
• RIV identification code: RIV/00216224:14310/19:00108351
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1016/j.csbj.2019.06.023
• UT WoS: 000504205700091
• Keywords in English: Fibrinolysis; Staphylokinase; Streptokinase; Thrombolysis; Tissue plasminogen activator; Urokinase
• Tags: rivok
• Tags: International impact, Reviewed

Abstract

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.

Links

• EF16_013/0001761, research and development project: Name: RECETOX RI
• LM2015047, research and development project: Name: Česká národní infrastruktura pro biologická data (Acronym: ELIXIR-CZ)

Investor: Ministry of Education, Youth and Sports of the CR, Czech National Infrastructure for Biological Data

• LM2015085, research and development project: Name: CERIT Scientific Cloud (Acronym: CERIT-SC)

Investor: Ministry of Education, Youth and Sports of the CR, CERIT Scientific Cloud

• TN01000013, research and development project: Name: Personalizovaná medicína - diagnostika a terapie

Investor: Technology Agency of the Czech Republic, Personalized Medicine – Diagnostics and Therapy