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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F22%3A00557418" target="_blank" >RIV/68081707:_____/22:00557418 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00159816:_____/22:00077750 RIV/00216224:14310/22:00126020

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S2001037022000794?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S2001037022000794?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.csbj.2022.03.004" target="_blank" >10.1016/j.csbj.2022.03.004</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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/).

Název v anglickém jazyce

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

Popis výsledku anglicky

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/).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Computational and Structural Biotechnology Journal

ISSN

2001-0370

e-ISSN

2001-0370

Svazek periodika

20

Číslo periodika v rámci svazku

MAR 2022

Stát vydavatele periodika

SE - Švédské království

Počet stran výsledku

12

Strana od-do

1366-1377

Kód UT WoS článku

000791774200010

EID výsledku v databázi Scopus

2-s2.0-85126623274