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Synthesis, molecular modeling and functional evaluation of a GnRH antagonist

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Abstract

In the present study, a series of novel Trp-Pro-Val containing peptides were prepared via solid-phase synthesis, and their structures were cyclized by a disulfide bridge, or modified by adding heterocycles of pyrazine, pyroglutamic acid, and 1,3,4-oxadiazoles to their N-terminus. These peptides were designed to antagonize gonadotropin-releasing hormone (GnRH)-receptor. Based on the detailed in vitro studies, incorporation of disulfide bond (peptide 1), the addition of pyroglutamate at the N-terminus (peptide 2), the addition of pyrazine at the N-terminus (peptide 3), and incorporation of GFRW to the N-terminus (peptide 5) were beneficial for inhibition of proliferation and induction of apoptosis in GnRH receptor-bearing cells including Hela and MCF-7 cell lines, whereas ineffective on Hep-G2 liver cancer and SW-48 colorectal adenocarcinoma cell lines devoiding of GnRH receptor. These results imply that the synthesized peptides 1, 2, 3, and 5 are GnRH antagonists and selective for GnRH receptors on the surface of tumor cells.

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References

  1. E.J. Neer, Protein Sci. 3, 3 (1994)

    Article  CAS  Google Scholar 

  2. H.E. Hamm, J. Biol. Chem. 273, 669 (1998)

    Article  CAS  Google Scholar 

  3. A. Thathiah, B. De Strooper, Sci. Signal. 2, re8 (2009).

  4. D.M. Harris, H.I. Cohn, S. Pesant, A.D. Eckhart, Clin. Sci. 115, 79 (2008)

    Article  CAS  Google Scholar 

  5. L. Nogués, J. Palacios-García, C. Reglero, V. Rivas, M. Neves, C. Ribas, P. Penela, F. Mayor Jr, in Seminars in Cancer Biology Elsevier, 2018, p. 78

  6. C. Liebmann, Curr. Pharm. Des. 10, 1937 (2004)

    Article  CAS  Google Scholar 

  7. F. Schneider, W. Tomek, C. Gründker, Theriogenology 66, 691 (2006)

    Article  CAS  Google Scholar 

  8. K. Eidne, C. Flanagan, N. Harris, R. Millar, J. Clin. Endocrinol. Metab. 64, 425 (1987)

    Article  CAS  Google Scholar 

  9. C. Gründker, G. Emons, Front. Endocrinol. 8, 187 (2017)

    Article  Google Scholar 

  10. C. Lambalk, F. Banga, J. Huirne, M. Toftager, A. Pinborg, R. Homburg, F. Van Der Veen, M. Van Wely, Hum. Reprod Update. 23, 560 (2017)

    Article  CAS  Google Scholar 

  11. F.-L. Tukun, D.E. Olberg, P.J. Riss, I. Haraldsen, A. Kaass, J. Klaveness, Molecules 22, 2188 (2017)

    Article  Google Scholar 

  12. S. Ma, S. Pradeep, A. Villar-Prados, Y. Wen, E. Bayraktar, L.S. Mangala, M.S. Kim, S.Y. Wu, W. Hu, C. Rodriguez-Aguayo, Mol. Cancer Ther. 18, 969 (2019)

    Article  CAS  Google Scholar 

  13. C.A. Hoeger, J.E. Rivier, P.G. Theobald, J.S. Porter, Peptide intermediates for making GnRH antagonists. US19960727798727, (1996)

  14. E. Lenci, A. Trabocchi, Chem. Soc. Rev. 49, 3262 (2020)

    Article  CAS  Google Scholar 

  15. V. Fathi Vavsari, S. Balalaie, J. Iran. Chem. Soc. (2021) https://doi.org/10.1007/s13738-021-02312-x

  16. M. Farhadpour, H. Hashempour, Z. Talebpour, A. Nazanin, M.S. Shushtarian, C.W. Gruber, A. Ghassempour, Anal. Biochem. 497, 83 (2016)

    Article  CAS  Google Scholar 

  17. H. Hashempour, J. Koehbach, N.L. Daly, A. Ghassempour, C.W. Gruber, Amino Acids 44, 581 (2013)

    Article  CAS  Google Scholar 

  18. M.A. Esmaeili, N. Abagheri-Mahabadi, H. Hashempour, M. Farhadpour, C.W. Gruber, A. Ghassempour, Fitoterapia 109, 162 (2016)

    Article  CAS  Google Scholar 

  19. M. Góngora-Benítez, J. Tulla-Puche, F. Albericio, Chem. Rev. 114, 901 (2014)

    Article  Google Scholar 

  20. A.R. Oyler, R.E. Naldi, J.R. Lloyd, D.A. Graden, C.J. Shaw, M.L. Cotter, J. Pharm. Sci. 80, 271 (1991)

    Article  CAS  Google Scholar 

  21. F. Hamdan, Z. Bigdeli, S. Balalaie, N. Sewald, C. Michalek, New J. Chem. 43, 2702 (2019)

    Article  CAS  Google Scholar 

  22. R.E. Wang, Y. Niu, H. Wu, M.N. Amin, J. Cai, Am. J. Nucl. Med. Mol. Imaging. 1, 36 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. F. Hamdan, Z. Bigdeli, S.M. Asghari, A. Sadremomtaz, S. Balalaie, ChemMedChem 14, 282 (2019)

    Article  CAS  Google Scholar 

  24. A. Corti, F. Curnis, Curr. Pharma. Biotech 12, 1128 (2011)

    Article  CAS  Google Scholar 

  25. W. Kim, M.H. Hecht, Proc. Natl. AcadSci. U.S.A. 103, 15824 (2006)

    Article  CAS  Google Scholar 

  26. M. Dolezal, J. Zitko, Expert Opin. Ther. Pat. 25, 33 (2015)

    Article  CAS  Google Scholar 

  27. F. Lumachi, D.A. Santeufemia, S.M. Basso, World J. Biological Chem. 6, 231 (2015)

    Article  Google Scholar 

  28. R. Eliasen, N.L. Daly, B.S. Wulff, T.L. Andresen, K.W. Conde-Frieboes, D.J. Craik, J. Biolog. Chem. 287, 40493 (2012)

    Article  CAS  Google Scholar 

  29. N. Uchida, K. Ishiguro, T. Suda, Y. Horie, M. Nishimura, Yonago. Acta Medica. 53, 71 (2010)

    CAS  Google Scholar 

  30. J.R. Frost, C.C. Scully, A.K. Yudin, Nat. Chem. 8, 1105 (2016)

    Article  CAS  Google Scholar 

  31. F. Golmohammadi, S. Balalaie, F. Hamdan, S. Maghari, New J. Chem. 42, 4344 (2018)

    Article  CAS  Google Scholar 

  32. S. Maghari, S. Ramezanpour, F. Darvish, S. Balalaie, F. Rominger, H.R. Bijanzadeh, Tetrahedron 69, 2075 (2013)

    Article  CAS  Google Scholar 

  33. A. Finch, K. Sedgley, S. Armstrong, C. Caunt, C. McArdle, Br. J. Pharmacol. 159, 751 (2010)

    Article  CAS  Google Scholar 

  34. A.R. Finch, K.R. Sedgley, C.J. Caunt, C.A. McArdle, J. Endocrinol. 196, 353 (2008)

    Article  CAS  Google Scholar 

  35. R. Eaveri, A. Ben-Yehudah, H. Lorberboum-Galski, Curr. Cancer Drug Targets. 4, 673 (2004)

    Article  CAS  Google Scholar 

  36. D. Pati, H. Habibi, Endocrinology 136, 75 (1995)

    Article  CAS  Google Scholar 

  37. S.E. Logue, M. Elgendy, S.J. Martin, Nat. Protoc. 4, 1383 (2009)

    Article  CAS  Google Scholar 

  38. C.M. Henry, E. Hollville, S.J. Martin, Methods 61, 90 (2013)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

S.B. thanks Alexander von Humboldt Foundation for the Linkage Research Group program.

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Authors and Affiliations

  1. Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Evin, Tehran, Iran

    Pegah Shakeri & Alireza Ghassempour

  2. Peptide Chemistry Research Institute, K. N. Toosi University of Technology, Tehran, Iran

    Pegah Shakeri, Vaezeh Fathi Vavsari, Farhad Golmohammadi & Saeed Balalaie

  3. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    S. Mohsen Asghari

  4. Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran

    Esmaeel Panahi Kokhdan

  5. Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Saeed Balalaie

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  1. Pegah Shakeri
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  2. S. Mohsen Asghari
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  3. Esmaeel Panahi Kokhdan
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  4. Vaezeh Fathi Vavsari
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  5. Farhad Golmohammadi
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  6. Alireza Ghassempour
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  7. Saeed Balalaie
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Correspondence to Alireza Ghassempour or Saeed Balalaie.

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Shakeri, P., Asghari, S.M., Panahi Kokhdan, E. et al. Synthesis, molecular modeling and functional evaluation of a GnRH antagonist. J IRAN CHEM SOC 19, 2705–2717 (2022). https://doi.org/10.1007/s13738-021-02484-6

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  • DOI: https://doi.org/10.1007/s13738-021-02484-6

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