Benzyl-para-di-[5-methyl-4-(n-octylamino) pyrimidin-2(1H)one] as an interferon beta (IFN-β) modulator.

Lena Trifonov, Mariya Yurchenko, Astrid Skjesol, Guy Cohen, Terje Espevik, Edward E Korshin, Lene Melsæther Grøvdal, Harald Husebye, Arie Gruzman

Molecular diversity 2022 Aug

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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. © 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Citation

Lena Trifonov, Mariya Yurchenko, Astrid Skjesol, Guy Cohen, Terje Espevik, Edward E Korshin, Lene Melsæther Grøvdal, Harald Husebye, Arie Gruzman. Benzyl-para-di-[5-methyl-4-(n-octylamino) pyrimidin-2(1H)one] as an interferon beta (IFN-β) modulator. Molecular diversity. 2022 Aug;26(4):2175-2188