Synthesis, molecular modeling and functional evaluation of a GnRH antagonist.

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. [ABSTRACT FROM AUTHOR]