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Investigation of Structure–Activity Relationships of Synthetic Anti‐Gonadotropin Releasing Hormone Vaccine Candidates
Author(s) -
Chang Chenghung,
Varamini Pegah,
Giddam Ashwini Kumar,
Mansfeld Friederike M.,
D'Occhio Michael J.,
Toth Istvan
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500036
Subject(s) - immunogenicity , epitope , lipopeptide , medicine , adjuvant , endocrinology , gonadotropin releasing hormone , receptor , antibody , hormone , follicular phase , chemistry , biology , immunology , luteinizing hormone , genetics , bacteria
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‐C 16 ‐C 16 , 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.