ArticlePharmaceutical research2005
A strategy to identify stable membrane-permeant peptide inhibitors of myosin light chain kinase.
Article in Pharmaceutical research, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- CDT ofToxins · 2023Article
- Unraveling the intestinal epithelial barrier in cyanotoxin microcystin-treated Caco-2 cell monolayers.Annals of the New York Academy of Sciences · 2022Article
- IP3 receptor orchestrates maladaptive vascular responses in heart failure.The Journal of clinical investigation · 2022Article
- A novel tumor suppressor role of myosin light chain kinase splice variants through downregulation of the TEAD4/CD44 axis.Carcinogenesis · 2021Article
- Gut microbial transcytosis induced by tumor necrosis factor-like 1A-dependent activation of a myosin light chain kinase splice variant contributes to IBD.Journal of Crohn's & colitis · 2021Article
- The scaffolding protein ZO-1 coordinates actomyosin and epithelial apical specializationsThe Journal of biological chemistry · 2018Article
- Listeria Adhesion Protein Induces Intestinal Epithelial Barrier Dysfunction for Bacterial Translocation.Cell host & microbe · 2018Article
- Enhanced paracellular transport of insulin can be achieved via transient induction of myosin light chain phosphorylation.Journal of controlled release : official journal of the Controlled Release Society · 2015Article
- Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux.Molecular biology of the cell · 2013Article
- Myosin light chain kinase signaling in endothelial barrier dysfunction.Medicinal research reviews · 2013Review
- Inhibition of long myosin light-chain kinase activation alleviates intestinal damage after binge ethanol exposure and burn injury.American journal of physiology. Gastrointestinal and liver physiology · 2012Article
- Myosin light chain kinase: pulling the strings of epithelial tight junction function.Annals of the New York Academy of Sciences · 2012Review
- TNFAIP3 maintains intestinal barrier function and supports epithelial cell tight junctions.PloS one · 2011Article
- Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury.American journal of respiratory cell and molecular biology · 2011Article
- Modulation of factors affecting optic nerve head astrocyte migration.Investigative ophthalmology & visual science · 2010Article
- Myosin light chain kinase inhibition: correction of increased intestinal epithelial permeability in vitro.Pharmaceutical research · 2008Article
- Rho activation regulates CXCL12 chemokine stimulated actin rearrangement and restitution in model intestinal epithelia.Laboratory investigation; a journal of technical methods and pathology · 2007Article
- Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application.The American journal of pathology · 2006Review
- Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo.The Journal of clinical investigation · 2006Article
- Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo.The Journal of clinical investigation · 2005Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeA peptide inhibitor of myosin light chain kinase (MLCK), termed membrane permeant inhibitor of myosin light chain kinase (PIK), has previously been demonstrated to correct paracellular barrier defects associated with in vitro cell models of infectious and inflammatory intestinal disease. The current study describes a strategy to identify stable analogues of PIK required for future in vivo studies that has resulted in the identification of two promising candidates.
methodsBecause PIK functions at an intracellular site of epithelial cells and is envisaged to be administered orally, hydrolysis patterns were determined for PIK in both extracts of homogenized Caco-2 (a human intestinal epithelial cell line) and in luminal secretions isolated from rat intestine. Based on these hydrolysis patterns, four peptides Ac-RKKYKYRRK-NH(2) (acetylated PIK), rkkykyrrk-NH(2) (D PIK), krrykykkr-NH(2) (Dreverse PIK), and RKKykyRRK-NH(2) (Dpalindrome PIK) were synthesised. Studies were carried out to determine the stability, activity, and selectivity of these PIK analogues.
resultsD PIK and Dreverse PIK had much longer half-lives of 3.6 and 13.4 h, respectively, compared to PIK, acetylated (Ac)-PIK, or Dpalindrome PIK. All PIK analogues inhibited MLCK potently, although D PIK was a slightly better inhibitor than the other analogues. Similarly, all PIK analogues enhanced paracellular barrier function in Caco-2 monolayers studied in vitro. No appreciable inhibition of cAMP-dependent protein kinase (PKA) or calcium/calmodulin-dependent protein kinase II (CaMPKII) was detected with any of the analogues.
conclusionsPIK is quickly degraded within two enzyme-containing preparations that represent different aspects of the intestinal environment. The PIK analogues D PIK and Dreverse PIK demonstrated extended half-lives in these enzyme preparations while retaining the biological activity and specificity of the parent PIK peptide.
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