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

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-11-16 DOI:10.1016/j.bmcl.2024.130032

Daram Jung, Sun Hee Jin, Yeasel Jeon, Joonseo Kim, Sungjin Ahn, Minsoo Noh

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Abstract

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.

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靶向 PDZK1IP1 的可穿透细胞肽核酸具有在人类角质细胞中抗炎的潜力。

PDZK1-交互蛋白1（PDZK1-interacting protein 1，PDZK1IP1）已成为皮肤炎症性疾病和上皮肿瘤的潜在治疗靶点。肽核酸是一类寡核苷酸疗法，以其与互补核酸序列的强大结合亲和力和抗核酸酶降解能力而著称。为了提高水溶性和细胞渗透性，我们通过将核碱基与伯胺链共轭合成了改性 PNA 寡聚体。一项使用荧光素标记的改性 PNA 寡聚体进行的研究表明，与未改性的 PNA 相比，改性 PNA 寡聚体在 HaCaT 细胞中的细胞渗透性明显增强。这些改性 PNA 低聚物能有效抑制 PDZK1IP1 基因的表达，减轻干扰素 γ（IFNγ）诱导的正常人角质形成细胞的炎症反应。这些发现表明，靶向 PDZK1IP1 的改良 PNAs 有可能应用于治疗皮肤炎症性疾病。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.