Computer-aided engineering of staphylokinase toward enhanced affinity and selectivity for plasmin

0557418 - BFÚ 2023 RIV SE eng J - Článek v odborném periodiku
Nikitin, D. - Mican, J. - Toul, J. - Bednar, D. - Pešková, Michaela - Kittová, Patrícia - Thalerová, Sandra - Víteček, Jan - Damborský, J. - Mikulik, R. - Fleishman, S. - Prokop, Z. - Marek, M.
Computer-aided engineering of staphylokinase toward enhanced affinity and selectivity for plasmin.
Computational and Structural Biotechnology Journal. Roč. 20, MAR 2022 (2022), s. 1366-1377. ISSN 2001-0370. E-ISSN 2001-0370
Institucionální podpora: RVO:68081707
Klíčová slova: angiographic patency trial * recombinant staphylokinase * mechanical stability * ischemic-stroke * activator * fibrin
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6, rok: 2022
Způsob publikování: Open access
https://www.sciencedirect.com/science/article/pii/S2001037022000794?via%3Dihub

Cardio-and cerebrovascular diseases are leading causes of death and disability, resulting in one of the highest socio-economic burdens of any disease type. The discovery of bacterial and human plasminogen activators and their use as thrombolytic drugs have revolutionized treatment of these pathologies. Fibrin specific agents have an advantage over non-specific factors because of lower rates of deleterious side effects. Specifically, staphylokinase (SAK) is a pharmacologically attractive indirect plasminogen activator protein of bacterial origin that forms stoichiometric noncovalent complexes with plasmin, promoting the conversion of plasminogen into plasmin. Here we report a computer-assisted re-design of the molecular surface of SAK to increase its affinity for plasmin. A set of computationally designed SAK mutants was produced recombinantly and biochemically characterized. Screening revealed a pharmacologically interesting SAK mutant with-7-fold enhanced affinity toward plasmin,-10-fold improved plasmin selectivity and moderately higher plasmin-generating efficiency in vitro. Collectively, the results obtained provide a framework for SAK engineering using computational affinity-design that could pave the way to next-generation of effective, highly selective, and less toxic thrombolytics.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Trvalý link: https://hdl.handle.net/11104/0339575