NMR-Guided Repositioning of Non-Steroidal Anti-Inflammatory Drugs into Tight Junction Modulators

Autor: Natsuko Goda, Kohki Kataoka, Hidekazu Hiroaki, Takeshi Tenno
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Magnetic Resonance Spectroscopy
PDZ Domains
Peptide
Pharmacology
Occludin
01 natural sciences
Madin Darby Canine Kidney Cells
lcsh:Chemistry
Mice
chemistry.chemical_compound
non-steroidal anti-inflammatory drugs
Fluorescein isothiocyanate
lcsh:QH301-705.5
Cells
Cultured
Spectroscopy
chemistry.chemical_classification
Tight junction
Chemistry
Anti-Inflammatory Agents
Non-Steroidal
General Medicine
drug absorption enhancer
Computer Science Applications
Paracellular transport
dynamic equilibrium of tight junction
hierarchical clustering
medicine.drug
tight junction integrity
PDZ domain
drug repositioning
Article
Catalysis
Tight Junctions
Inorganic Chemistry
03 medical and health sciences
Dogs
medicine
Animals
Humans
Physical and Theoretical Chemistry
Claudin
Molecular Biology
NMR screening
010405 organic chemistry
Organic Chemistry
Epithelial Cells
0104 chemical sciences
030104 developmental biology
Flufenamic acid
lcsh:Biology (General)
lcsh:QD1-999
Zonula Occludens-1 Protein
Caco-2 Cells
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 5
International Journal of Molecular Sciences, Vol 22, Iss 2583, p 2583 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22052583
Popis: Bioavailability is a major bottleneck in the clinical application of medium molecular weight therapeutics, including protein and peptide drugs. Paracellular transport of these molecules is hampered by intercellular tight junction (TJ) complexes. Therefore, safe chemical regulators for TJ loosening are desired. Here, we showed a potential application of select non-steroidal anti-inflammatory drugs (NSAIDs) as TJ modulators. Based on our previous observation that diclofenac and flufenamic acid directly bound various PDZ domains with a broad specificity, we applied solution nuclear magnetic resonance techniques to examine the interaction of other NSAIDs and the first PDZ domain (PDZ1) of zonula occludens (ZO)-1, ZO-1(PDZ1). Inhibition of ZO-1(PDZ1) is expected to provide loosening of the epithelial barrier function because the domain plays a crucial role in maintaining TJ integrity. Accordingly, diclofenac and indomethacin were found to decrease the subcellular localization of claudin (CLD)-2 but not occludin and ZO-1 at the apicolateral intercellular compartment of Madin–Darby canine kidney (MDCK) II cells. These NSAIDs exhibited 125–155% improved paracellular efflux of fluorescein isothiocyanate insulin for the Caco-2 cell monolayer. We propose that these NSAIDs can be repurposed as drug absorption enhancers for peptide drugs.
Databáze: OpenAIRE
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