A novel conformation in a highly potent, constrained gonadotropin-releasing hormone antagonist

Jose Rizo-Rey, R. Bryan Sutton, Joshua Breslau, Steven C. Koerber, John Porter, Arnold T. Hagler, Jean E. Rivier, Lila M. Gierasch

Research output: Contribution to journalArticle

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Abstract

Through design, synthesis, and biological testing of constrained gonadotropin releasing hormone (GnRH) antagonists, we are studying the structural requirements for biological activity. Here we describe the conformational analysis in solution of a highly potent, dicyclic GnRH antagonist, dicyclo(4-10/5,5'-8)[Ac-D-2Nal1,D-pClPhe2,D3Pal3,Asp4,Glu5(Gly),D -Arg6,Dbu8,Dpr10]GnRH (1), using NMR spectroscopy. The dicyclic part of this molecule adopts a preferred conformation containing a type II β turn around residues 5-6, nested with a type I' β turn around residues 6-7,and a type II β-turn-like structure involving residue 9 and the side chain of residue 10, which is stabilized by hydrogen bonds between Leu7 NH/Asp4 CO, Dbu8 NH(δ)/Glu5 CO, and Dpr10 NH(γ)/Dbu8 CO. This is a novel conformation that had not been observed previously in any constrained GnRH antagonist and is remarkably different from that found for another dicyclic(4-10/5-8) GnRH antagonist with very similar sequence, dicyclo(410/5-8)[Ac-D-2Nal1,D-pClPhe2,D-Trp3,Asp4,Glu5,D-Asp6,Ly s8,Dpr10]GnRH (2) (Bienstock et al. J. Med. Chem. 1993, 36, 3265-3273). The conformation of 2 contains a type II' β turn around residues 6-7, which had been proposed to be essential for GnRH activity. These results are important for our general understanding of polypeptide conformation, since they show that the dicyclo(4-10/5-8) backbone can adopt more than one family of conformations despite its dicyclic nature, and from the point of view of the design of GnRH antagonists, since they suggest that the presence of a turn around residues 6-7, rather than the type of β turn, may be necessary for biological activity.

Original languageEnglish (US)
Pages (from-to)970-976
Number of pages7
JournalJournal of the American Chemical Society
Volume118
Issue number5
DOIs
StatePublished - 1996

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Hormone Antagonists
Gonadotropin-Releasing Hormone
Conformations
Carbon Monoxide
Bioactivity
Polypeptides
Nuclear magnetic resonance spectroscopy
Hydrogen
Hydrogen bonds
Magnetic Resonance Spectroscopy
Peptides
Molecules
Testing

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Rizo-Rey, J., Sutton, R. B., Breslau, J., Koerber, S. C., Porter, J., Hagler, A. T., ... Gierasch, L. M. (1996). A novel conformation in a highly potent, constrained gonadotropin-releasing hormone antagonist. Journal of the American Chemical Society, 118(5), 970-976. https://doi.org/10.1021/ja953207e

A novel conformation in a highly potent, constrained gonadotropin-releasing hormone antagonist. / Rizo-Rey, Jose; Sutton, R. Bryan; Breslau, Joshua; Koerber, Steven C.; Porter, John; Hagler, Arnold T.; Rivier, Jean E.; Gierasch, Lila M.

In: Journal of the American Chemical Society, Vol. 118, No. 5, 1996, p. 970-976.

Research output: Contribution to journalArticle

Rizo-Rey, J, Sutton, RB, Breslau, J, Koerber, SC, Porter, J, Hagler, AT, Rivier, JE & Gierasch, LM 1996, 'A novel conformation in a highly potent, constrained gonadotropin-releasing hormone antagonist', Journal of the American Chemical Society, vol. 118, no. 5, pp. 970-976. https://doi.org/10.1021/ja953207e
Rizo-Rey, Jose ; Sutton, R. Bryan ; Breslau, Joshua ; Koerber, Steven C. ; Porter, John ; Hagler, Arnold T. ; Rivier, Jean E. ; Gierasch, Lila M. / A novel conformation in a highly potent, constrained gonadotropin-releasing hormone antagonist. In: Journal of the American Chemical Society. 1996 ; Vol. 118, No. 5. pp. 970-976.
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AU - Porter, John

AU - Hagler, Arnold T.

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N2 - Through design, synthesis, and biological testing of constrained gonadotropin releasing hormone (GnRH) antagonists, we are studying the structural requirements for biological activity. Here we describe the conformational analysis in solution of a highly potent, dicyclic GnRH antagonist, dicyclo(4-10/5,5'-8)[Ac-D-2Nal1,D-pClPhe2,D3Pal3,Asp4,Glu5(Gly),D -Arg6,Dbu8,Dpr10]GnRH (1), using NMR spectroscopy. The dicyclic part of this molecule adopts a preferred conformation containing a type II β turn around residues 5-6, nested with a type I' β turn around residues 6-7,and a type II β-turn-like structure involving residue 9 and the side chain of residue 10, which is stabilized by hydrogen bonds between Leu7 NH/Asp4 CO, Dbu8 NH(δ)/Glu5 CO, and Dpr10 NH(γ)/Dbu8 CO. This is a novel conformation that had not been observed previously in any constrained GnRH antagonist and is remarkably different from that found for another dicyclic(4-10/5-8) GnRH antagonist with very similar sequence, dicyclo(410/5-8)[Ac-D-2Nal1,D-pClPhe2,D-Trp3,Asp4,Glu5,D-Asp6,Ly s8,Dpr10]GnRH (2) (Bienstock et al. J. Med. Chem. 1993, 36, 3265-3273). The conformation of 2 contains a type II' β turn around residues 6-7, which had been proposed to be essential for GnRH activity. These results are important for our general understanding of polypeptide conformation, since they show that the dicyclo(4-10/5-8) backbone can adopt more than one family of conformations despite its dicyclic nature, and from the point of view of the design of GnRH antagonists, since they suggest that the presence of a turn around residues 6-7, rather than the type of β turn, may be necessary for biological activity.

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