Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Fig. 1
Scheme 3
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

All data that were shown in the manuscript and synthesized compounds are available.

Abbreviations

MI:

Myocardial ischemia

TLR4:

Toll-like receptor 4

PRRs:

Pattern recognition receptors

LPS:

Lipopolysaccharide

TIR:

Toll/interleukin-1 receptor

Mal:

MyD88-adaptor-like

TRAM:

TRIF-related adaptor molecule

TRIF:

TIR-domain-containing adapter-inducing interferon-β

IFN-β:

Type I interferon beta

PMA:

Phorbol 12-myristate-13-acetate

LDH:

Lactate dehydrogenase

IFNAR:

Interferon-α/β receptor

TBK-1:

TANK-binding kinase-1

TAK-1:

Transforming growth factor beta-activated kinase 1

IRF3:

Interferon Regulatory Factor 3

p38 MAPK:

P38 mitogen-activated protein kinase

IκBα:

Kappa light polypeptide gene enhancer in B-cells inhibitor alpha

MDA5/RIG-I:

Melanoma-differentiation-associated gene 5/retinoic-acid-inducible protein-1

BBB:

Blood–brain barrier

APCs:

Antigen-presenting cells

DQT:

6-Chloroethylureidoethyldiquino[3,2-b;2',3'-e][1,4]thiazine

References

  1. Trifonov L, Nudelman V, Zhenin M, Matsree E, Afri M, Schmerling B, Cohen G, Jozwiak K, Weitman M, Korshin E, Senderowitz H, Shainberg A, Hochhauser E, Gruzman A (2018) Structurally simple, readily available peptidomimetic 1-Benzyl-5-methyl-4-(n-octylamino)pyrimidin-2(1H)-one exhibited efficient cardioprotection in a myocardial ischemia (MI) mouse model. J Med Chem 61(24):11309–11326. https://doi.org/10.1021/acs.jmedchem.8b01471

    Article  CAS  PubMed  Google Scholar 

  2. Hadden MK, Blagg BS (2008) Dimeric approaches to anti-cancer chemotherapeutics. Anticancer Agents Med Chem 8:807–816. https://doi.org/10.2174/187152008785914743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arav-Boger R, He R, Chiou CJ, Liu J, Woodard L, Rosenthal A, Jones-Brando L, Forman M, Posner G (2010) Artemisinin-derived dimers have greatly improved anti-cytomegalovirus activity compared to artemisinin monomers. PLoS ONE 5(4):e10370. https://doi.org/10.1371/journal.pone.0010370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhu Y, Deng J, Nan ML, Zhang J, Okekunle A, Li JY, Yu XQ, Wang PH (2019) The interplay between pattern recognition receptors and autophagy in inflammation. Adv Exp Med Biol 1209:79–108. https://doi.org/10.1007/978-981-15-0606-2_6

    Article  CAS  PubMed  Google Scholar 

  5. Park BS, Lee JO (2013) Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med 45(12):e66–e66. https://doi.org/10.1038/emm.2013

    Article  PubMed  PubMed Central  Google Scholar 

  6. Husebye ES, Anderson MS (2010) Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity 32(4):479–487. https://doi.org/10.1016/j.immuni.2010.03.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R (2008) TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol 9(4):361–368. https://doi.org/10.1038/ni1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125(5):943–955. https://doi.org/10.1016/j.cell.2006.03.047

    Article  CAS  PubMed  Google Scholar 

  9. Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104(4):487–501. https://doi.org/10.1016/s0092-8674(01)00237-9

    Article  CAS  PubMed  Google Scholar 

  10. Kumaran Satyanarayanan S, El Kebir D, Soboh S, Butenko S, Sekheri M, Saadi J, Peled N, Assi S, Othman A, Schif-Zuck S, Feuermann Y, Barkan D, Sher N, Filep JG, Ariel A (2019) IFN-β is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation. Nat Commun 10(1):3471. https://doi.org/10.1038/s41467-019-10903-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tamassia N, Le Moigne V, Calzetti F, Donini M, Gasperini S, Ear T, Cloutier A, Martinez FO, Fabbri M, Locati M, Mantovani A, McDonald PP, Cassatella MA (2007) The MyD88-independent pathway is not mobilized in human neutrophils stimulated via TLR4. J Immunol 178(11):7344–7356. https://doi.org/10.4049/jimmunol.178.11.7344

    Article  CAS  PubMed  Google Scholar 

  12. Kohro T, Tanaka T, Murakami T, Wada Y, Aburatani H, Hamakubo T, Kodama TA (2004) Comparison of differences in the gene expression profiles of phorbol 12-myristate 13-acetate differentiated THP-1 cells and human monocyte-derived macrophage. J Atheroscler Thromb 11(2):88–97. https://doi.org/10.5551/jat.11.88

    Article  CAS  PubMed  Google Scholar 

  13. Skjesol A, Yurchenko M, Bösl K, Gravastrand C, Nilsen KE, Grøvdal LM, Agliano F, Patane F, Lentini G, Kim H, Teti G, Kumar Sharma A, Kandasamy RK, Sporsheim B, Starheim KK, Golenbock DT, Stenmark H, McCaffrey M, Espevik T, Husebye H (2019) The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2. PLoS Pathog 15:e1007684. https://doi.org/10.1371/journal.ppat.1007684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yurchenko M, Skjesol A, Ryan L, Richard GM, Kandasamy RK, Wang N, Terhorst C, Husebye H, Espevik T (2018) SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling in human macrophages. J Cell Biol 217:1411–1429. https://doi.org/10.1083/jcb.201707027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Haji Abdolvahab M, Mofrad MR, Schellekens H (2016) Interferon beta: from molecular level to therapeutic effects. Int Rev Cell Mol Biol 326:343–372. https://doi.org/10.1016/bs.ircmb.2016.06.001

    Article  CAS  PubMed  Google Scholar 

  16. Escobar G, Moi D, Ranghetti A, Ozkal-Baydin P, Squadrito ML, Kajaste-Rudnitski A, Bondanza A, Gentner B, De Palma M, Mazzieri R, Naldini L (2014) Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression. Sci Transl Med 6(217):217ra3. https://doi.org/10.1126/scitranslmed.3006353

    Article  CAS  PubMed  Google Scholar 

  17. Ojha PK, Kar S, Krishna JG, Roy K, Leszczynski J (2021) Therapeutics for COVID-19: from computation to practices—where we are, where we are heading to. Mol Divers 25:625–659. https://doi.org/10.1007/s11030-020-10134-x

    Article  CAS  PubMed  Google Scholar 

  18. Kashyap K, Siddiqi MI (2021) Recent trends in artificial intelligence-driven identification and development of anti-neurodegenerative therapeutic agents. Mol Divers 25:1517–1539. https://doi.org/10.1007/s11030-021-10274-8

    Article  CAS  PubMed  Google Scholar 

  19. McKay FC, Hoe E, Parnell G, Gatt P, Schibeci SD, Stewart GJ, Booth DR (2013) IL7Rα expression and upregulation by IFNβ in dendritic cell subsets is haplotype-dependent. PLoS ONE 8(10):e77508. https://doi.org/10.1371/journal.pone.0077508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vallittu AM, Saraste M, Airas L (2007) CCR7 expression on peripheral blood lymphocytes is up-regulated following treatment of multiple sclerosis with interferon-beta. Neurol Res 29(8):763–766. https://doi.org/10.1179/016164107X228633

    Article  CAS  PubMed  Google Scholar 

  21. Dhib-Jalbut S, Marks S (2010) Interferon-beta mechanisms of action in multiple sclerosis. Neurology 74(Suppl 1):S17-24. https://doi.org/10.1212/WNL.0b013e3181c97d99

    Article  CAS  PubMed  Google Scholar 

  22. Huang H, Ito K, Dangond F, Dhib-Jalbut S (2013) Effect of interferon beta-1a on B7.1 and B7.2 B-cell expression and its impact on T-cell proliferation. J Neuroimmunol 258(1–2):27–31. https://doi.org/10.1016/j.jneuroim.2013.02.010

    Article  CAS  PubMed  Google Scholar 

  23. Meinl E, Krumbholz M, Hohlfeld R (2006) B lineage cells in the inflammatory central nervous system environment: migration, maintenance, local antibody production, and therapeutic modulation. Ann Neurol 59(6):880–892. https://doi.org/10.1002/ana.20890

    Article  CAS  PubMed  Google Scholar 

  24. Vervoordeldonk MJ, Aalbers CJ, Tak pp. (2009) Interferon beta for rheumatoid arthritis: new clothes for an old kid on the block. Ann Rheum Dis 68(2):157–158. https://doi.org/10.1136/ard.2008.097899

    Article  CAS  PubMed  Google Scholar 

  25. Rauch I, Müller M, Decker T (2013) The regulation of inflammation by interferons and their STATs. JAKSTAT 2(1):e23820. https://doi.org/10.4161/jkst.23820

    Article  PubMed  PubMed Central  Google Scholar 

  26. Huys L, Van Hauwermeiren F, Dejager L, Dejonckheere E, Lienenklaus S, Weiss S, Leclercq G, Libert C (2009) Type I interferon drives tumor necrosis factor-induced lethal shock. J Exp Med 206(9):1873–1882. https://doi.org/10.1084/jem.20090213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Strzadala L, Fiedorowicz A, Wysokinska E, Ziolo E, Grudzień M, Jelen M, Pluta K, Morak-Mlodawska B, Zimecki M, Kalas W (2018) An anti-inflammatory Azaphenothiazine inhibits interferon β expression and CXCL10 production in KERTr cells. Molecules 23(10):2443. https://doi.org/10.3390/molecules23102443

    Article  CAS  PubMed Central  Google Scholar 

  28. Gottlieb HE, Kotlyar V, Nudelman A (1997) NMR chemical shifts of common laboratory solvents as trace impurities. J Org Chem 62(21):7512–7515. https://doi.org/10.1021/jo971176v

    Article  CAS  PubMed  Google Scholar 

  29. Ngwendson JN, Atemnkeng WN, Schultze CM, Banerjee A (2006) A convenient synthesis of symmetric 1,2-diarylethenes from arylmethyl phosphonium salts. Org Lett 8(18):4085–4088. https://doi.org/10.1021/ol061594z

    Article  CAS  PubMed  Google Scholar 

  30. Campeau E, Ruhl VE, Rodier F, Smith CL, Rahmberg BL, Fuss JO, Campisi J, Yaswen P, Cooper PK, Kaufman PD (2009) A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS ONE 4:e6529. https://doi.org/10.1371/journal.pone.0006529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ehrnström B, Beckwith KS, Yurchenko M, Moen SH, Kojen JF, Lentini G, Teti G, Damås JK, Espevik T, Stenvik J (2017) Toll-like receptor 8 is a major sensor of group B Streptococcus but not Escherichia coli in human primary monocytes and macrophages. Front Immunol 8:1243. https://doi.org/10.3389/fimmu.2017.01243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Mr. Steven Manch for the English editing. We also wish to thank Dr. Marina Vainberg and Dr. Alexander Vainberg for providing the space and the scientific equipment/environment for this work.

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).

Author information

Author notes

  1. Lena Trifonov and Mariya Yurchenko have contributed equally.

Authors and Affiliations

  1. Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, 5290002, Ramat-Gan, Israel

    Lena Trifonov, Edward E. Korshin & Arie Gruzman

  2. Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway

    Mariya Yurchenko, Astrid Skjesol, Terje Espevik, Lene Melsæther Grøvdal & Harald Husebye

  3. The Skin Research Institute, The Dead-Sea & Arava Science Center, 86910, Masada, Israel

    Guy Cohen

Authors
  1. Lena Trifonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariya Yurchenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Astrid Skjesol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guy Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Terje Espevik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edward E. Korshin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lene Melsæther Grøvdal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Harald Husebye
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Arie Gruzman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The project idea was generated by A. G. and H. H. The synthetic chemistry work was performed by L. T. and E. E. K. The THP-1 TLR8 cell line was made by M. Y. L. The THP-1 TLR9mCherry cell line was made by M. G. The biological research was carried out by M. Y., A. S., and G. C. T. E. All authors contributed to the manuscript writing and review process.

Corresponding authors

Correspondence to Harald Husebye or Arie Gruzman.

Ethics declarations

Conflict of interest

Authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 7863 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Trifonov, L., Yurchenko, M., Skjesol, A. et al. Benzyl-para-di-[5-methyl-4-(n-octylamino) pyrimidin-2(1H)one] as an interferon beta (IFN-β) modulator. Mol Divers 26, 2175–2188 (2022). https://doi.org/10.1007/s11030-021-10324-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-021-10324-1

Keywords

Search

Navigation