Design of potent cyclic gonadotropin releasing hormone antagonists

Abstract

In the course of our studies toward the development of novel analogs of the decapeptide gonadotropin releasing hormone (GnRH), we have examined a hexapeptide that is an antagonist of endothelin (ET). It was found that this peptide, Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide 1), binds specifically to the pituitary GnRH receptor. Moreover, peptide 1 exhibits a GnRH agonistic activity (i.e., it induces luteinizing hormone release from rat pituitary). This activity is mediated directly by the GnRH receptor and is suppressed by a GnRH antagonist. Removal of the acetyl group of peptide 1 results in a hexapeptide (peptide 2) with binding properties similar to those of GnRH but with a diminished affinity toward the ET receptor. Several other ET antagonists were screened for a potential interaction with the GnRH receptor. Two of these, the hexapeptide PD145065 and the cyclic pentapeptide BQ-123, expressed GnRH agonistic activity at micromolar concentrations in vitro. BQ-123, previously approved for trials on humans as an ET antagonist, is demonstrated to act in vivo as a GnRH agonist, in a dose that was demonstrated previously as the minimal required dose for significant ET antagonism. The GnRH agonistic activity of ET antagonists may therefore result in interference with the physiological control of the reproductive system. Such effects may be most severe when ET antagonists are used chronically. Thus, the major practical message of this study is the need to circumvent the potential side effects of ET antagonist-based drugs.

Human Growth Hormone-Releasing Hormone hGHRH(1−29)-NH2: Systematic Structure−Activity Relationship Studies

“…Therefore, the polar directionality of the bridging element aligned with the overall peptide dipole will also influence bioactivity as shown earlier. 70 …”

CuI‐Catalyzed Azide–Alkyne Intramolecular i‐to‐(i+4) Side‐Chain‐to‐Side‐Chain Cyclization Promotes the Formation of Helix‐Like Secondary Structures

“…Intramolecular side-chain-to-side-chain cyclizations through bridges include those formed by the redox susceptible and hydrophobic disulfide bonds between pairs of cysteines, [2] the polar lactams between pairs of ω-amino-and ω-carboxyl-α-amino acids, [3] and the all hydrophobic "stapled" rings between pairs of non-coded ω-olefin-derivatized α-amino acids. [4] To enable unambiguously targeted intramolecular side-chain-to-side-chain disulfide-and lactambridged cyclizations, orthogonal protection strategies are employed.…”

Structure–Function Studies of Linear and Cyclized Peptide Antagonists of the GnRH Receptor

“…For the cyclo [1][2][3][4][5][6][7][8][9][10] peptides D-23620 (Cyclorelix) and D-24236 (Cycloantarelix), this strategy was not successful since binding affinity was reduced up to 80-fold. Nevertheless, highly potent cyclo [1][2][3][4] and cyclo [4 -10] peptides were described in the literature and structural analysis of a cyclo [4 -10] analog revealed the presence of a ␤-hairpin conformation within residues 5-8, stabilized by two hydrogen bonds, with a type IIЈ ␤-turn around positions 6 and 7 (27,28,30,31). Consistent with these data, cyclo [3][4][5][6][7][8] decapeptides were found to be highly potent (27,28,32).…”