Investigation of Structure–Activity Relationships of Synthetic Anti-Gonadotropin Releasing Hormone Vaccine Candidates

Chenghung Chang, Pegah Varamini, Ashwini Kumar Giddam, Friederike M. Mansfeld, Michael J. D'Occhio, Istvan Toth

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4 Citations (Scopus)

Abstract

The immunoneutralization of gonadotropin-releasing hormone (GnRH) can be used for the treatment of human hormone-dependent male and female cancers or as immunocontraceptives in animals. Vaccine candidates 1 [Th(K-LP)GnRH], 2 [GnRH(K-LP)Th], 3 [GnRH(K-Th)LP], and 4 [Th(K-GnRH)LP] (for which K=lysine, LP=lipopeptide Ser-Ser-C16-C16, and Th=T helper cell epitope influenza HA2), were synthesized by assembling a CD4+ T helper cell epitope (Th), GnRH, and an adjuvanting lipid moiety (LP) in various spatial arrangements. All compounds were efficiently taken up by antigen-presenting cells with significant immunogenicity without an external adjuvant. Compounds 2, 3, and 4, in which GnRH is conjugated through its C terminus, produced higher GnRH-specific antibody responses than construct 1, in which the GnRH moiety is conjugated through its N terminus. All four constructs induced a significant antiproliferative effect (up to 55 %) on GnRH-receptor-positive LNCaP cells, but showed weaker activity in the GnRH-receptor-negative SKOV-3 cell line. Marked degenerative changes were observed in morphology and follicular development in the ovaries of immunized mice, with approximately 30 % higher degenerative antral and atretic follicles.

Original languageEnglish
Pages (from-to)901-910
Number of pages10
JournalChemMedChem
Volume10
Issue number5
DOIs
Publication statusPublished - 1 May 2015
Externally publishedYes

Keywords

  • GnRH
  • immunocontraception
  • lipopeptides
  • self-adjuvanting
  • subunit vaccines

Cite this

Chang, C., Varamini, P., Giddam, A. K., Mansfeld, F. M., D'Occhio, M. J., & Toth, I. (2015). Investigation of Structure–Activity Relationships of Synthetic Anti-Gonadotropin Releasing Hormone Vaccine Candidates. ChemMedChem, 10(5), 901-910. https://doi.org/10.1002/cmdc.201500036