Abstract: 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. Graphic abstract: [Figure not available: see fulltext.]
|Number of pages||14|
|State||Published - Aug 2022|
Bibliographical noteFunding Information:
This study was partially supported by KAMIN (Israel Ministry of Industry, Trade, and Labor, (Grant 56324, A. G.). G. C. was partially supported by the Israeli Ministry of Science and Technology (Grant 580458776). The Israel Ministry of Immigration and Integration through a Kamea fellowship supported E. E. K. (Grant 8279). M. Y., A. S., T. E., and H. H. were supported by the Research Council of Norway (Grant 223255/F50 and 275876).
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
- Pyrimidine derivatives