Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Anti-Inflammatory Activity of Cell-Penetrating Peptide Nucleic Acids Targeting Indoleamine 2,3-Dioxygenase 1 in IFNγ-Treated Human Keratinocytes

  • Daram Jung (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • Sungjin Ahn (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • In Guk Park (Natural Products Research Institute, College of Pharmacy, Seoul National University) ;
  • Yeasel Jeon (OliPass Corporation) ;
  • Sangbong Lee (OliPass Corporation) ;
  • Minsoo Noh (Natural Products Research Institute, College of Pharmacy, Seoul National University)
  • Received : 2024.11.04
  • Accepted : 2024.12.12
  • Published : 2025.05.01
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Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that plays a pivotal role in immune regulation by metabolizing tryptophan into kynurenine, leading to T cell suppression and promoting immune tolerance. However, persistent activation of IDO1 can lead to prolonged immune stimulation in inflammatory conditions such as skin diseases and chronic inflammation. In this study, we developed modified peptide nucleic acids (PNAs) conjugated with cationic lipid chains to target IDO1 pre-mRNA and evaluated their anti-inflammatory effects in human keratinocytes. The modified PNAs demonstrated enhanced solubility, robust binding affinity, and effective penetration into keratinocytes. Quantitative PCR results showed significant downregulation of IDO1 and pro-inflammatory cytokines such as IL-6, IL-8, and PTGS2 in interferon γ (IFNγ)-treated keratinocytes. These findings suggest that cell-penetrating PNAs targeting IDO1 hold potential as a therapeutic approach for inflammatory skin disorders and chronic inflammation.

Keywords

Acknowledgement

This study was partly supported by the National Research Foundation (NRF) of Korea (and RS-2024-00399364) and by the Ministry of Health & Welfare, Republic of Korea (RS-2024-00351858).

References

  1. Avitabile, C., Moggio, L., Malgieri, G., Capasso, D., Di Gaetano, S., Saviano, M., Pedone, C. and Romanelli, A. (2012) γ sulphate PNA (PNA S): highly selective DNA binding molecule showing promising antigene activity. PLoS One 7, e35774. https://doi.org/10.1371/journal.pone.0035774
  2. Cesario, A., Rocca, B. and Rutella, S. (2011) The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)- 2 in chronic inflammation and cancer. Curr. Med. Chem. 18, 2263-2271. https://doi.org/10.2174/092986711795656063
  3. Dragulescu-Andrasi, A., Rapireddy, S., Frezza, B. M., Gayathri, C., Gil, R. R. and Ly, D. H. (2006) A simple γ-backbone modification preorganizes peptide nucleic acid into a helical structure. J. Am. Chem. Soc. 128, 10258-10267. https://doi.org/10.1021/ja0625576
  4. Fujiwara, Y., Kato, S., Nesline, M. K., Conroy, J. M., DePietro, P., Pabla, S. and Kurzrock, R. (2022) Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy. Cancer Treat. Rev. 110, 102461. https://doi.org/10.1016/j.ctrv.2022.102461
  5. Guo, G., Sun, L., Yang, L. and Xu, H. (2019) IDO1 depletion induces an anti-inflammatory response in macrophages in mice with chronic viral myocarditis. Cell Cycle 18, 2598-2613. https://doi.org/10.1080/15384101.2019.1652471
  6. Gupta, A., Quijano, E., Liu, Y., Bahal, R., Scanlon, S. E., Song, E., Hsieh, W.-C., Braddock, D. E., Ly, D. H., Saltzman, W. M. and Glazer, P. M. (2017) Anti-tumor activity of miniPEG-γ-modified PNAs to inhibit microRNA-210 for cancer therapy. Mol. Ther. Nucleic Acids 9, 111-119. https://doi.org/10.1016/j.omtn.2017.09.001
  7. Ito, H., Ando, T., Ogiso, H., Arioka, Y., Saito, K. and Seishima, M. (2015) Inhibition of indoleamine 2,3-dioxygenase activity accelerates skin wound healing. Biomaterials 53, 221-228. https://doi.org/10.1016/j.biomaterials.2015.02.098
  8. Lauffer, M. C., van Roon-Mom, W. and Aartsma-Rus, A. (2024) Possibilities and limitations of antisense oligonucleotide therapies for the treatment of monogenic disorders. Commun. Med. 4, 6.
  9. Muller, A. J., Sharma, M. D., Chandler, P. R., DuHadaway, J. B., Everhart, M. E., Johnson, B. A., III, Kahler, D. J., Pihkala, J., Soler, A. P., Munn, D. H., Prendergast, G. C. and Mellor, A. L. (2008) Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3-dioxygenase. Proc. Natl. Acad. Sci. U. S. A. 105, 17073-17078. https://doi.org/10.1073/pnas.0806173105
  10. Nandhini, K. P., Al Shaer, D., Albericio, F. and de la Torre, B. G. (2023) The challenge of peptide nucleic acid synthesis. Chem. Soc. Rev. 52, 2764-2789. https://doi.org/10.1039/D2CS00049K
  11. Opitz, C. A., Somarribas Patterson, L. F., Mohapatra, S. R., Dewi, D. L., Sadik, A., Platten, M. and Trump, S. (2020) The therapeutic potential of targeting tryptophan catabolism in cancer. Br. J. Cancer 122, 30-44. https://doi.org/10.1038/s41416-019-0664-6
  12. Öztürk, Ö., Lessl, A.-L., Höhn, M., Wuttke, S., Nielsen, P. E., Wagner, E. and Lächelt, U. (2023) Peptide nucleic acid-zirconium coordination nanoparticles. Sci. Rep. 13, 14222.
  13. Panjkovich, A. and Melo, F. (2005) Comparison of different melting temperature calculation methods for short DNA sequences. Bioinformatics 21, 711-722. https://doi.org/10.1093/bioinformatics/bti066
  14. Pfaffl, M. W., Horgan, G. W. and Dempfle, L. (2001) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 29, 2002-2007.
  15. Platten, M., Nollen, E. A. A., Röhrig, U. F., Fallarino, F. and Opitz, C. A. (2019) Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat. Rev. Drug Discov. 18, 379-401. https://doi.org/10.1038/s41573-019-0016-5
  16. Podlaski, F., Cornwell, S., Wong, K., McKittrick, B., Kim, J.-H., Jung, D., Jeon, Y., Jung, K.-B., Tolias, P. and Windsor, W. T. (2023) Peptide nucleic acids containing cationic/amino-alkyl modified bases promote enhanced hybridization kinetics and thermodynamics with single-strand DNA. ACS Omega 8, 33426-33436. https://doi.org/10.1021/acsomega.3c03184
  17. Prendergast, G. C., Malachowski, W. P., DuHadaway, J. B. and Muller, A. J. (2017) Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 77, 6795-6811. https://doi.org/10.1158/0008-5472.CAN-17-2285
  18. Prendergast, G. C., Metz, R. and Muller, A. J. (2010) Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway. Am. J. Pathol. 176, 2082-2087. https://doi.org/10.2353/ajpath.2010.091173
  19. Quemener, A. M., Centomo, M. L., Sax, S. L. and Panella, R. (2022) Small drugs, huge impact: the extraordinary impact of antisense oligonucleotides in research and drug development. Molecules 27, 536. https://doi.org/10.3390/molecules27020536
  20. Roberts, T. C., Langer, R. and Wood, M. J. A. (2020) Advances in oligonucleotide drug delivery. Nat. Rev. Drug Discov. 19, 673-694. https://doi.org/10.1038/s41573-020-0075-7
  21. Shaikh, A. Y., Björkling, F., Nielsen, P. E. and Franzyk, H. (2021) Optimized synthesis of Fmoc/Boc-protected PNA monomers and their assembly into PNA oligomers. Eur. J. Org. Chem. 2021, 2792-2801. https://doi.org/10.1002/ejoc.202100278
  22. Shon, W.-J., Lee, Y.-K., Shin, J. H., Choi, E. Y. and Shin, D.-M. (2015) Severity of DSS-induced colitis is reduced in Ido1-deficient mice with down-regulation of TLR-MyD88-NF-kB transcriptional networks. Sci. Rep. 5, 17305. https://doi.org/10.1038/srep17305
  23. Shayesteh, S., Guillemin, G. J., Rashidian, A., Faghir-Ghanesefat, H., Mani, A. R., Tavangar, S. M. and Dehpour, A. R. (2021) 1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis. Eur. J. Pharmacol. 908, 174309. https://doi.org/10.1016/j.ejphar.2021.174309
  24. Staudacher, A., Hinz, T., Novak, N., von Bubnoff, D. and Bieber, T. (2015) Exaggerated IDO1 expression and activity in Langerhans cells from patients with atopic dermatitis upon viral stimulation: a potential predictive biomarker for high risk of eczema herpeticum. Allergy 70, 1432-1439. https://doi.org/10.1111/all.12699
  25. Terada, C., Oh, K., Tsubaki, R., Chan, B., Aibara, N., Ohyama, K., Shibata, M.-A., Wada, T., Harada-Shiba, M., Yamayoshi, A. and Yamamoto, T. (2023) Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry. Nat. Commun. 14, 7972.
  26. Thomson, S. A., Josey, J. A., Cadilla, R., Gaul, M. D., Hassman, C. F., Luzzio, M. J., Pipe, A. J., Reed, K. L., Ricca, D. J., Wiethe, R. W. and Noble, S. A. (1995) Fmoc mediated synthesis of peptide nucleic acids. Tetrahedron 51, 6179-6194. https://doi.org/10.1016/0040-4020(95)00286-H
  27. Zhai, L., Ladomersky, E., Lenzen, A., Nguyen, B., Patel, R., Lauing, K. L., Wu, M. and Wainwright, D. A. (2018) IDO1 in cancer: a Gemini of immune checkpoints. Cell. Mol. Immunol. 15, 447-457. https://doi.org/10.1038/cmi.2017.143
  28. Zhai, Y., Li, S., Wang, H. and Shan, Y. (2024) Revealing the dynamic mechanism of cell-penetrating peptides across cell membranes at the single-molecule level. J. Mater. Chem. B 12, 5589-5593. https://doi.org/10.1039/D4TB00522H