Abstract
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.
Highlights
Peptide and protein therapeutics, including non-natural cyclic peptides, are an emerging class of pharmaceuticals in drug discovery for unmet medical needs [1,2,3]
We found a weak interaction between zonula occludens (ZO)-1(PDZ1) and five non-steroidal anti-inflammatory drugs (NSAIDs), aceclofenac to ZO-1(PDZ1)
We propose an alternative mechanism of NSAID-derived tight junction (TJ) opening by the direct binding of the first PSD-95/Discs large/and ZO-1 (PDZ) domain of ZO-1, which prevents TJ biogenesis
Summary
Peptide and protein therapeutics, including non-natural cyclic peptides, are an emerging class of pharmaceuticals in drug discovery for unmet medical needs [1,2,3]. They are characterized by a large molecular surface with different functional groups that can provide higher affinity and specificity to the therapeutic target proteins compared to the authentic “rule-of-five” (Ro5) drugs. Such “beyond-Ro5 drugs” have a critical drawback, which is their poor bioavailability.
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