Investigation of Structure–Activity Relationships of Synthetic Anti‐Gonadotropin Releasing Hormone Vaccine Candidates. Issue 5 (25th March 2015)

• Record Type: Journal Article
• Authors: Chang, Chenghung; Varamini, Pegah; Giddam, Ashwini Kumar; Mansfeld, Friederike M.; D'Occhio, Michael J.; Toth, Istvan
• Is Part Of: ChemMedChem. Volume 10:Issue 5(2015:May)
• Page Start: 901
• Page End: 910
• Publication Date: 2015-03-25
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500036
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <bold>1</bold> [Th(K‐LP)GnRH], <bold>2</bold> [GnRH(K‐LP)Th], <bold>3</bold> [GnRH(K‐Th)LP], and <bold>4</bold> [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 <bold>2</bold>, <bold>3</bold>, and <bold>4</bold>, in which GnRH is conjugated through its C terminus, produced higher GnRH‐specific antibody responses than construct <bold>1</bold>, 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.</p> </abstract>