title: Investigation of structure-activity relationships of synthetic anti-gonadotropin releasing hormone vaccine candidates.
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.
authors: School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072 (Australia).
authors: Chenghung
authors: C
authors: Chang
authors: Pegah
authors: P
authors: Varamini
authors: Ashwini Kumar
authors: AK
authors: Giddam
authors: Friederike M
authors: FM
authors: Mansfeld
authors: Michael J
authors: MJ
authors: D'Occhio
authors: Istvan
authors: I
authors: Toth
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006801:Humans; D007273:Injections, Intramuscular; D008264:Macrophages / Q000276:immunology; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology*
chemical_list: D014614:Vaccines, Synthetic; D007987:Gonadotropin-Releasing Hormone
keywords: GnRH; immunocontraception; lipopeptides; self-adjuvanting; subunit vaccines