Benzyl-para-di-[5-methyl-4-(n-octylamino) pyrimidin-2(1H)one] as an interferon beta (IFN-β) modulator
| Autor: | Guy Cohen, Lene Melsæther Grøvdal, Terje Espevik, Arie Gruzman, Astrid Skjesol, Edward E. Korshin, Lena Trifonov, Harald Husebye, Mariya Yurchenko |
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| Rok vydání: | 2021 |
| Předmět: |
Peptidomimetic
medicine.medical_treatment Pharmacology Catalysis Inorganic Chemistry Mice Drug Discovery medicine CXCL10 Animals Cardioprotective Agent Physical and Theoretical Chemistry Molecular Biology Chemistry Organic Chemistry MDA5 Biological activity General Medicine Interferon-beta Shock Septic Toll-Like Receptor 4 Cytokine TLR4 Cytokines Tumor necrosis factor alpha Peptidomimetics Information Systems Signal Transduction |
| Zdroj: | Molecular diversity. 26(4) |
| ISSN: | 1573-501X |
| Popis: | IFN-β is a cytokine that plays a significant role in the immune system. Inhibition of IFN-β might be used as a therapeutic approach to treat septic shock. A peptidomimetic previously developed by our research team, 1-benzyl-5-methyl-4-(n-octylamino)pyrimidin-2(1H)-one (LT87), was used as an cardioprotective agent in a myocardial ischemia (MI) mouse model. We have developed new LT87 derivatives by synthetizing its dimers in an attempt to extend its structural variety and enhance its biological activity. A dimeric derivative, LT127, exhibited a dose-dependent inhibition of LPS-mediated IFN-β and subsequent CXCL10 mRNA transcription. The effect was selective and transduced through TLR4- and TRAM/TRIF-mediated signaling, with no significant effect on MyD88-dependent signaling. However, this effect was not specific to TLR4, since a similar effect was observed both on TLR8- and MDA5/RIG-I-stimulated IFN-β expression. Nevertheless, LT127 might serve as a drug candidate, specifically as an inhibitor for IFN-β production in order to develop a novel therapeutic approach to prevent septic shock. |
| Databáze: | OpenAIRE |
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