Cell penetrable peptide nucleic acids targeting PDZK1IP1 with anti-inflammatory potential in human keratinocytes

• Published in: Bioorganic & medicinal chemistry letters Vol. 115; p. 130032
• Main Authors: Jung, Daram, Jin, Sun Hee, Jeon, Yeasel, Kim, Joonseo, Ahn, Sungjin, Noh, Minsoo
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-01-2025
• Subjects: Anti-sense oligonucleotide; Cell penetration; PDZK1IP1; Peptide nucleic acids; Skin inflammation; IFNγ; CPP; TNFα; Skin inflammation; NHKs; SPPS; ASOs; PDZK1IP1; PTGS2; Anti-sense oligonucleotide; Cell penetration; PNAs; Boc; Tm; Fmoc; Peptide nucleic acids; Fmoc-Aeg-O-Allyl
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2024.130032

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•A primary amine chain was introduced into the nucleobase to synthesize a modified PNA.•Chemical modification enhanced the water solubility and cellular permeability of PNAs.•PDZK1IP1-targeting PNAs have therapeutic potential in inflammatory skin diseases.
PDZK1-interacting protein 1 (PDZK1IP1) has emerged as a potential therapeutic target for skin inflammatory diseases and epithelial tumors. This study investigates the modulation of PDZK1IP1 gene expression using peptide nucleic acids (PNAs), a class of oligonucleotide therapeutics known for their robust binding affinity to complementary nucleic acid sequences and their resistance to degradation by nucleases. To enhance water solubility and cellular permeability, modified PNA oligomers were synthesized by conjugating nucleobases with primary amine chains. A study using a fluorescein-labeled modified PNA oligomer demonstrated significantly enhanced cellular permeability in HaCaT cells compared to the unmodified PNA. These modified PNA oligomers effectively suppressed PDZK1IP1 gene expression and alleviated interferon γ (IFNγ)-induced inflammatory responses in normal human keratinocytes. These findings suggest the potential application of modified PNAs targeting PDZK1IP1 in the treatment of skin inflammatory diseases.