A Novel Conformation in a Highly Potent, Constrained Gonadotropin-Releasing Hormone Antagonist
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- 作者：Josep Rizo ; R. Bryan Sutton ; Joshua Breslau ; Steven C. Koerber ; John Porter ; Arnold T. Hagler ; Jean E. Rivier ; and Lila M. Gierasch
- 刊名：Journal of the American Chemical Society
- 出版年：1996
- 出版时间：February 7, 1996
- 年：1996
- 卷：118
- 期：5
- 页码：970 - 976
- 全文大小：213K
- 年卷期：v.118,no.5(February 7, 1996)
- ISSN：1520-5126
文摘
Through design, synthesis, and biological testing of constrainedgonadotropin releasing hormone (GnRH)antagonists, we are studying the structural requirements for biologicalactivity. Here we describe the conformationalanalysis in solution of a highly potent, dicyclic GnRH antagonist,dicyclo(4-10/5,5'-8)[Ac-D-2Nal1,D-pClPhe2,D-3Pal3,Asp4,Glu5(Gly),D-Arg6,Dbu8,Dpr10]GnRH(1), using NMR spectroscopy. The dicyclic part of thismoleculeadopts a preferred conformation containing a type II 
fchars/beta2.gif" BORDER=0 ALIGN="middle"> turn aroundresidues 5-6, nested with a type I' fchars/beta2.gif" BORDER=0 ALIGN="middle"> turn aroundresidues 6-7, and a type II fchars/beta2.gif" BORDER=0 ALIGN="middle">-turn-like structure involving residue9 and the side chain of residue 10, which isstabilized by hydrogen bonds between Leu7NH/Asp4 CO, Dbu8NHfchars/delta.gif" BORDER=0 >/Glu5 CO, and Dpr10NHfchars/gamma.gif" BORDER=0 >/Dbu8 CO. This isa novel conformation that had not been observed previously in anyconstrained GnRH antagonist and is remarkablydifferent from that found for another dicyclic (4-10/5-8) GnRHantagonist with very similar sequence, dicyclo(4-10/5-8)[Ac-D-2Nal1,D-pClPhe2,D-Trp3,Asp4,Glu5,D-Arg6,Lys8,Dpr10]GnRH(2) (Bienstock et al. J. Med. Chem.1993,36, 3265-3273). The conformation of 2contains a type II' fchars/beta2.gif" BORDER=0 ALIGN="middle"> turn around residues 6-7, which had beenproposedto be essential for GnRH activity. These results are important forour general understanding of polypeptideconformation, since they show that the dicyclo(4-10/5-8) backbonecan adopt more than one family of conformationsdespite its dicyclic nature, and from the point of view of the designof GnRH antagonists, since they suggest that thepresence of a turn around residues 6-7, rather than the type of fchars/beta2.gif" BORDER=0 ALIGN="middle">turn, may be necessary for biological activity.
fchars/beta2.gif" BORDER=0 ALIGN="middle"> turn aroundresidues 5-6, nested with a type I' fchars/beta2.gif" BORDER=0 ALIGN="middle"> turn aroundresidues 6-7, and a type II fchars/beta2.gif" BORDER=0 ALIGN="middle">-turn-like structure involving residue9 and the side chain of residue 10, which isstabilized by hydrogen bonds between Leu7NH/Asp4 CO, Dbu8NHfchars/delta.gif" BORDER=0 >/Glu5 CO, and Dpr10NHfchars/gamma.gif" BORDER=0 >/Dbu8 CO. This isa novel conformation that had not been observed previously in anyconstrained GnRH antagonist and is remarkablydifferent from that found for another dicyclic (4-10/5-8) GnRHantagonist with very similar sequence, dicyclo(4-10/5-8)[Ac-D-2Nal1,D-pClPhe2,D-Trp3,Asp4,Glu5,D-Arg6,Lys8,Dpr10]GnRH(2) (Bienstock et al. J. Med. Chem.1993,36, 3265-3273). The conformation of 2contains a type II' fchars/beta2.gif" BORDER=0 ALIGN="middle"> turn around residues 6-7, which had beenproposedto be essential for GnRH activity. These results are important forour general understanding of polypeptideconformation, since they show that the dicyclo(4-10/5-8) backbonecan adopt more than one family of conformationsdespite its dicyclic nature, and from the point of view of the designof GnRH antagonists, since they suggest that thepresence of a turn around residues 6-7, rather than the type of fchars/beta2.gif" BORDER=0 ALIGN="middle">turn, may be necessary for biological activity.