Structural investigation of Cetrorelix, a new potent and long-acting LH-RH antagonist.
The new decapeptide SB-75 (INN: Cetrorelix) has been characterized as a potent antagonist of luteinizing-hormone releasing hormone (LH-RH). Such derivatives are of great medicinal interest owing to their potential application in areas such as hormone-dependent tumors, uterine fibroids, and in diseases and conditions which result from inappropriate hormone levels or which can be treated by suppression of estrogens. SB-75 is the subject of intensive ongoing clinical evaluation and is an accepted standard for the design of new LH-RH antagonists. We characterized SB-75 by means of modern MS and NMR techniques to demonstrate the significance of both sequencing methods on a complicated unnatural decapeptide. Our structural elucidations with nuclear Overhauser (NOE) experiments revealed clear evidence for a highly flexible molecule with no single predominant conformation even in sodium dodecyl sulfate (SDS) mimicking a cellular membrane.
Müller
A
A
Degussa AG, Hanau-Wolfgang, Germany.
Busker
E
E
Engel
J
J
Kutscher
B
B
Bernd
M
M
Schally
A V
AV
D000595:Amino Acid Sequence; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011966:Receptors, LHRH / Q000378:metabolism; D012997:Solvents
D011966:Receptors, LHRH; D012997:Solvents; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix