Design of Peptidase-resistant Peptide Inhibitors of Myosin Light Chain Kinaseстатья
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Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 9 января 2019 г.
Авторы:
Khapchaev A.Y. ,
Kazakova О.А.,
Samsonov M.V. ,
Sidorova M.V. ,
Bushuev V.N. ,
Vilitkevich E.L. ,
Az’muko A.A. ,
Molokoedov A.S. ,
Bespalova Zh D. ,
Shirinsky V.P.
Журнал:
Journal of Peptide Science
Том:
22
Номер:
11-12
Год издания:
2016
Издательство:
John Wiley & Sons Inc.
Местоположение издательства:
United States
Первая страница:
673
Последняя страница:
681
DOI:
10.1002/psc.2928
Аннотация:
Myosin light chain kinase (MLCK) is a key regulator of various forms of cell motility including smooth muscle contraction, cell migration, cytokinesis, receptor capping, secretion, etc. Inhibition of MLCK activity in endothelial and epithelial monolayers using cell-permeant peptide Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys (PIK, Peptide Inhibitor of Kinase) allows protecting the barrier capacity, suggesting a potential medical use of PIK. However, low stability of L-PIK in a biological milieu prompts for development of more stable L-PIK analogues for use as experimental tools in basic and drug-oriented biomedical research. Previously,we designed PIK1, H-(NαMe)Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH2, that was 2.5-fold more resistant to peptidases in human plasma in vitro than L-PIK and equal to it as MLCK inhibitor. In order to further enhance proteolytic stability of PIK inhibitor,we designed the set of six site-protected peptides based on L-PIK and PIK1 degradation patterns in human plasma as revealed by 1H-NMR analysis. Implemented modifications increased half-live of the PIK-related peptides in plasma about 10-fold, and these compounds retained 25–100% of L-PIK inhibitory activity toward MLCK in vitro. Based on stability and functional activity ranking, PIK2, H-(NαMe)Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-D-Arg-Lys-NH2, was identified as the most stable and effective L-PIK analogue. PIK2 was able to decrease myosin light chain phosphorylation in endothelial cells stimulated with thrombin, and this effect correlated with the inhibition by PIK2 of thrombin-induced endothelial hyperpermeability in vitro. Therefore, PIK2 could be used as novel alternative to other cell-permeant inhibitors of MLCK in cell culture-based and in vivo studies where MLCK catalytic activity inhibition is required. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Добавил в систему:
Хапчаев Аскер Юсуфович