Cell-penetrating anti-sense peptide nucleic acids targeting sulfatase 2 inhibit adipogenesis in human mesenchymal stem cells

• Published in: Bioorganic & medicinal chemistry 2024-12, Vol.116, p.118009, Article 118009
• Main Authors: Jung, Daram, Ahn, Sungjin, Jeon, Yeasel, Kim, Minhee, Park, In Guk, Kim, Areum, Noh, Minsoo
• Format: Article
• Language: English
• Subjects: Adipogenesis; Adipogenesis - drug effects; Anti-sense oligonucleotide; Binding affinity; Cell Differentiation - drug effects; Cell-Penetrating Peptides - chemical synthesis; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - metabolism; Cell-Penetrating Peptides - pharmacology; Cells, Cultured; Human bone marrow mesenchymal stem cells; Humans; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Molecular Structure; Peptide nucleic acids; Peptide Nucleic Acids - chemical synthesis; Peptide Nucleic Acids - chemistry; Peptide Nucleic Acids - pharmacology; Structure-Activity Relationship; Sulfatase 2; Sulfatases - antagonists & inhibitors; Sulfatases - metabolism
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2024.118009

[Display omitted] •Modified PNA oligomers penetrate cellular membrane.•Expression of SULF2 is reciprocally regulated during adipo-osteogenic differentiation.•SULF2 targeting PNA oligomer inhibit adipogenesis in hBM-MSCs.•SULF2 targeting PNA oligomer has therapeutic potential in obesity. Targeting the genes regulate the lineage commitment of human mesenchymal stem cells (hMSCs) to adipocytes provides a promising strategy for addressing obesity. In this study, we investigated the therapeutic potential of cell-penetrating anti-sense peptide nucleic acids (PNAs) designed to enhance solubility and hybridization properties, specifically targeting sulfatase 2 (SULF2), a potential reciprocal regulator of adipocyte and osteoblast differentiation in hMSCs. Cell-penetrating modified PNA oligomers effectively inhibit SULF2 gene transcription, leading to significant reductions in adiponectin protein synthesis and intracellular lipid droplet accumulation during adipogenesis in human bone marrow-derived MSCs (hBM-MSCs). Notably, PNA oligomer compound 5 exhibited the most potent anti-adipogenic activity, with an IC50 value of 0.28 μM. These findings show the potential of SULF2-targeting cell-penetrating PNA oligomers as novel therapeutic agents for obesity-related metabolic diseases.