SpringerLink
Log in

KDM5 Family Demethylase Inhibitor KDOAM-25 Reduces Entry of SARS-CoV-2 Pseudotyped Viral Particles into Cells

  • Published:
Bulletin of Experimental Biology and Medicine Aims and scope

We studied the effect of KDM5 family demethylase inhibitors (JIB-04, PBIT, and KDOAM-25) on the penetration of SARS-CoV-2 pseudotyped viruses into differentiated Caco-2 cells and HEK293T cells with ACE2 hyperexpression. The above drugs were not cytotoxic. Only KDOAM-25 significantly reduced virus entry into the cells. The expression of ACE2 mRNA in Caco-2 significantly increased, while TMPRSS2 expression did not significantly change under these conditions. In differentiated Caco-2 cells, KDOAM-25 did not affect the expression of BRCA1, CDH1, TP53, SNAI1, VIM, and UGCG genes, for which an association with knockdown or overexpression of KDM5 demethylases or with the action of demethylase inhibitors had previously been shown. In undifferentiated Caco-2 cells, the expression of BRCA1, SNAI1, VIM, and CDH1 was significantly increased under the action of KDOAM-25.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Laurie MT, Liu J, Sunshine S, Peng J, Black D, Mitchell AM, Mann SA, Pilarowski G, Zorn KC, Rubio L, Bravo S, Marquez C, Sabatino JJ, Mittl K, Petersen M, Havlir D, DeRisi J. SARS-CoV-2 variant exposures elicit antibody responses with differential cross-neutralization of established and emerging strains including Delta and Omicron. J. Infect. Dis. 2022;225(11):1909-1914. https://doi.org/10.1093/infdis/jiab635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ashour NA, Abo Elmaaty A, Sarhan AA, Elkaeed EB, Moussa AM, Erfan IA, Al-Karmalawy AA. A systematic review of the global intervention for SARS-CoV-2 combating: from drugs repurposing to Molnupiravir approval. Drug Des. Devel. Ther. 2022;16:685-715. https://doi.org/10.2147/DDDT.S354841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huang S, Fishell G. In SARS-CoV-2, astrocytes are in it for the long haul. Proc. Natl Acad. Sci. USA. 2022;119(30):e2209130119. https://doi.org/10.1073/pnas.2209130119

  4. Knyazev E, Nersisyan S, Tonevitsky A. Endocytosis and transcytosis of SARS-CoV-2 across the intestinal epithelium and other tissue barriers. Front. Immunol. 2021;12:636966. https://doi.org/10.3389/fimmu.2021.636966

  5. Nersisyan S, Shkurnikov M, Turchinovich A, Knyazev E, Tonevitsky A. Integrative analysis of miRNA and mRNA sequencing data reveals potential regulatory mechanisms of ACE2 and TMPRSS2. PLoS One. 2020;15(7):e0235987. https://doi.org/10.1371/journal.pone.0235987

  6. Tumber A, Nuzzi A, Hookway ES, Hatch SB, Velupillai S, Johansson C, Kawamura A, Savitsky P, Yapp C, Szykowska A, Wu N, Bountra C, Strain-Damerell C, Burgess-Brown NA, Ruda GF, Fedorov O, Munro S, England KS, Nowak RP, Schofield CJ, La Thangue NB, Pawlyn C, Davies F, Morgan G, Athanasou N, Müller S, Oppermann U, Brennan PE. Potent and selective KDM5 inhibitor stops cellular demethylation of H3K4me3 at transcription start sites and proliferation of MM1S myeloma cells. Cell Chem. Biol. 2017;24(3):371-380. https://doi.org/10.1016/j.chembiol.2017.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zheng YC, Chang J, Wang LC, Ren HM, Pang JR, Liu HM. Lysine demethylase 5B (KDM5B): A potential anti-cancer drug target. Eur. J. Med. Chem. 2019;161:131-140. https://doi.org/10.1016/j.ejmech.2018.10.040

    Article  CAS  PubMed  Google Scholar 

  8. Brewitz L, Tumber A, Pfeffer I, McDonough M.A, Schofield CJ. Aspartate/asparagine-β-hydroxylase: a high-throughput mass spectrometric assay for discovery of small molecule inhibitors. Sci. Rep. 2020;10(1):8650. https://doi.org/10.1038/s41598-020-65123-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Betari N, Sahlholm K, Ishizuka Y, Teigen K, Haavik J. Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis. Future Med. Chem. 2020;12(16):1461-1474. https://doi.org/10.4155/fmc-2020-0127

    Article  CAS  PubMed  Google Scholar 

  10. Wang L, Chang J, Varghese D, Dellinger M, Kumar S, Best AM, Ruiz J, Bruick R, Peña-Llopis S, Xu J, Babinski DJ, Frantz DE, Brekken RA, Quinn AM, Simeonov A, Easmon J, Martinez ED. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. Nat. Commun. 2013;4:2035. https://doi.org/10.1038/ncomms3035

    Article  CAS  PubMed  Google Scholar 

  11. Chen M, Zhang XE. Construction and applications of SARS-CoV-2 pseudoviruses: a mini review. Int. J. Biol. Sci. 2021;17(6):1574-1580. https://doi.org/10.7150/ijbs.59184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rosa RB, Dantas WM, do Nascimento JCF, da Silva MV, de Oliveira RN, Pena LJ. In vitro and in vivo models for studying SARS-CoV-2, the etiological agent responsible for COVID-19 pandemic. Viruses. 2021;13(3):379. https://doi.org/10.3390/v13030379.

  13. Nikulin SV, Knyazev EN, Gerasimenko TN, Shilin SA, Gazizov IN, Zakharova GS, Poloznikov AA, Sakharov DA. Impedance spectroscopy and transcriptome analysis of choriocarcinoma BeWo b30 as a model of human placenta. Mol. Biol. (Mosk). 2019;53(3):467-475. https://doi.org/10.1134/S0026898419030133

    Article  CAS  PubMed  Google Scholar 

  14. Knyazev EN, Nyushko KM, Alekseev BY, Samatov TR, Shkurnikov MY. Suppression of ITGB4 gene expression in PC-3 cells with short interfering RNA induces changes in the expression of β-integrins associated with RGD-receptors. Bull. Exp. Biol. Med. 2015;159(4):541-545. https://doi.org/10.1007/s10517-015-3011-9

    Article  CAS  PubMed  Google Scholar 

  15. Sayegh J, Cao J, Zou MR, Morales A, Blair LP, Norcia M, Hoyer D, Tackett AJ, Merkel JS, Yan Q. Identification of small molecule inhibitors of Jumonji AT-rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high throughput screen. J. Biol. Chem. 2013;288(13):9408-9417. https://doi.org/10.1074/jbc.M112.419861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim MS, Cho HI, Yoon HJ, Ahn YH, Park EJ, ** YH, Jang YK. JIB-04, a small molecule histone demethylase inhibitor, selectively targets colorectal cancer stem cells by inhibiting the Wnt/β-catenin signaling pathway. Sci. Rep. 2018;8(1):6611. https://doi.org/10.1038/s41598-018-24903-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Müller MR, Burmeister A, Skowron MA, Stephan A, Bremmer F, Wakileh GA, Petzsch P, Köhrer K, Albers P, Nettersheim D. Therapeutical interference with the epigenetic landscape of germ cell tumors: a comparative drug study and new mechanistical insights. Clin. Epigenetics. 2022;14(1):5. https://doi.org/10.1186/s13148-021-01223-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nersisyan SA, Shkurnikov MY, Osipyants AI, Vechorko VI. Role of ACE2/TMPRSS2 genes regulation by intestinal microRNA isoforms in the COVID-19 pathogenesis. Bulletin of RSMU. 2020;(2):16-18. https://doi.org/10.24075/brsmu.2020.024

  19. Baddock HT, Brolih S, Yosaatmadja Y, Ratnaweera M, Bielinski M, Swift LP, Cruz-Migoni A, Fan H, Keown JR, Walker AP, Morris GM, Grimes JM, Fodor E, Schofield CJ, Gileadi O, McHugh PJ. Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification. Nucleic Acids Res. 2022;50(3):1484-1500. https://doi.org/10.1093/nar/gkab1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Son J, Huang S, Zeng Q, Bricker TL, Case JB, Zhou J, Zang R, Liu Z, Chang X, Darling TL, Xu J, Harastani HH, Chen L, Gomez Castro MF, Zhao Y, Kohio HP, Hou G, Fan B, Niu B, Guo R, Rothlauf PW, Bailey AL, Wang X, Shi PY, Martinez ED, Brody SL, Whelan SPJ, Diamond MS, Boon ACM, Li B, Ding S. JIB-04 has broad-spectrum antiviral activity and inhibits SARS-CoV-2 replication and coronavirus pathogenesis. mBio. 2022;13(1):e0337721. https://doi.org/10.1128/mbio.03377-21

  21. Beacon TH, Delcuve GP, Davie JR. Epigenetic regulation of ACE2, the receptor of the SARS-CoV-2 virus1. Genome. 2021;64(4):386-399. https://doi.org/10.1139/gen-2020-0124

    Article  CAS  PubMed  Google Scholar 

  22. Knyazev E, Maltseva D, Raygorodskaya M, Shkurnikov M. HIF-dependent NFATC1 activation upregulates ITGA5 and PLAUR in intestinal epithelium in inflammatory bowel disease. Front. Genet. 2021;12:791640. https://doi.org/10.3389/fgene.2021.791640

  23. Yamane K, Tateishi K, Klose RJ, Fang J, Fabrizio LA, Erdjument-Bromage H, Taylor-Papadimitriou J, Tempst P, Zhang Y. PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. Mol. Cell. 2007;25(6):801-812. https://doi.org/10.1016/j.molcel.2007.03.001

    Article  CAS  PubMed  Google Scholar 

  24. Rajput K, Ansari MN, Jha SK, Medatwal N, Sharma P, Datta S, Kar A, Pani T, Cholke K, Rana K, Khan A, Mukherjee G, Deo SVS, Prabhu JS, Mukhopadhyay A, Bajaj A, Dasgupta U. RICTOR drives ZFX-mediated ganglioside biosynthesis to promote breast cancer progression. bioRxiv. 2022.01.10.475595. https://doi.org/10.1101/2022.01.10.475595

  25. Bamodu OA, Huang WC, Lee WH, Wu A, Wang LS, Hsiao M, Yeh CT, Chao TY. Aberrant KDM5B expression promotes aggressive breast cancer through MALAT1 overexpression and downregulation of hsa-miR-448. BMC Cancer. 2016;16:160. https://doi.org/10.1186/s12885-016-2108-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dey BK, Stalker L, Schnerch A, Bhatia M, Taylor-Papidimitriou J, Wynder C. The histone demethylase KDM5b/JARID1b plays a role in cell fate decisions by blocking terminal differentiation. Mol. Cell. Biol. 2008;28(17):5312-5327. https://doi.org/10.1128/MCB.00128-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dabiri Y, Gama-Brambila RA, Taškova K, Herold K, Reuter S, Adjaye J, Utikal J, Mrowka R, Wang J, Andrade-Navarro MA, Cheng X. Imidazopyridines as potent KDM5 demethylase inhibitors promoting reprogramming efficiency of human iPSCs. iScience. 2019;12:168-181. https://doi.org/10.1016/j.isci.2019.01.012

  28. Kuo KT, Huang WC, Bamodu OA, Lee WH, Wang CH, Hsiao M, Wang LS, Yeh CT. Histone demethylase JARID1B/KDM5B promotes aggressiveness of non-small cell lung cancer and serves as a good prognostic predictor. Clin. Epigenetics. 2018;10(1):107. https://doi.org/10.1186/s13148-018-0533-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schonfeld M, Averilla J, Gunewardena S, Weinman SA, Tikhanovich I. Male-specific activation of lysine demethylases 5B and 5C mediates alcohol-induced liver injury and hepatocyte dedifferentiation. Hepatol. Commun. 2022;6(6):1373-1391. https://doi.org/10.1002/hep4.1895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nikulin SV, Mnafki (Krainova) NA, Shilin SA, Gazizov IN, Maltseva DV. Ribosome inactivation and the integrity of the intestinal epithelial barrier. Mol. Biol. (Mosk). 2018;52(4):675-682. https://doi.org/10.1134/S0026898418040146

Download references

Author information

Authors and Affiliations

  1. M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    E. N. Knyazev, R. S. Kalinin, V. A. Abrikosova & Yu.A. Mokrushina

  2. Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia

    E. N. Knyazev & S. A. Tonevitskaya

Authors
  1. E. N. Knyazev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. S. Kalinin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. A. Abrikosova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu.A. Mokrushina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. A. Tonevitskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. N. Knyazev.

Additional information

Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 1, pp. 40-46, March, 2023

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Knyazev, E.N., Kalinin, R.S., Abrikosova, V.A. et al. KDM5 Family Demethylase Inhibitor KDOAM-25 Reduces Entry of SARS-CoV-2 Pseudotyped Viral Particles into Cells. Bull Exp Biol Med 175, 150–156 (2023). https://doi.org/10.1007/s10517-023-05827-w

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10517-023-05827-w

Keywords

Search

Navigation