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

doi:10.1007/s11030-021-10324-1

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

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.]

Original language	English
Pages (from-to)	2175-2188
Number of pages	14
Journal	Molecular Diversity
Volume	26
Issue number	4
DOIs	https://doi.org/10.1007/s11030-021-10324-1
State	Published - Aug 2022

Bibliographical note

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

Funding

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).

Funders	Funder number
Israel Ministry of Immigration and Integration	8279
KAMIN
Ministry of Industry, Trade and Labor	56324
Norges Forskningsråd	275876, 223255/F50
Ministry of science and technology, Israel	580458776

Keywords

CXCL10
Interferon-β
Pyrimidine derivatives
TLR
TNF

Access to Document

10.1007/s11030-021-10324-1

Cite this

@article{aa515a9f72ee453ea0a18be74f63c6ac,

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

abstract = "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.]",

keywords = "CXCL10, Interferon-β, Pyrimidine derivatives, TLR, TNF",

author = "Lena Trifonov and Mariya Yurchenko and Astrid Skjesol and Guy Cohen and Terje Espevik and Korshin, {Edward E.} and Gr{\o}vdal, {Lene Mels{\ae}ther} and Harald Husebye and Arie Gruzman",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.",

year = "2022",

month = aug,

doi = "10.1007/s11030-021-10324-1",

language = "אנגלית",

volume = "26",

pages = "2175--2188",

journal = "Molecular Diversity",

issn = "1381-1991",

publisher = "Springer Nature",

number = "4",

}

TY - JOUR

T1 - Benzyl-para-di-[5-methyl-4-(n-octylamino) pyrimidin-2(1H)one] as an interferon beta (IFN-β) modulator

AU - Trifonov, Lena

AU - Yurchenko, Mariya

AU - Skjesol, Astrid

AU - Cohen, Guy

AU - Espevik, Terje

AU - Korshin, Edward E.

AU - Grøvdal, Lene Melsæther

AU - Husebye, Harald

AU - Gruzman, Arie

PY - 2022/8

Y1 - 2022/8

N2 - 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.]

AB - 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.]

KW - CXCL10

KW - Interferon-β

KW - Pyrimidine derivatives

KW - TLR

KW - TNF

UR - http://www.scopus.com/inward/record.url?scp=85117284793&partnerID=8YFLogxK

U2 - 10.1007/s11030-021-10324-1

DO - 10.1007/s11030-021-10324-1

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34668104

AN - SCOPUS:85117284793

SN - 1381-1991

VL - 26

SP - 2175

EP - 2188

JO - Molecular Diversity

JF - Molecular Diversity

IS - 4

ER -

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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this