Structural elucidation of Leuprolide and its analogues in solution: insight into their bioactive conformation (Journal article)

Laimou, D. K./ Katsara, M./ Matsoukas, M. T. I./ Apostolopoulos, V./ Troganis, A. N./ Tselios, T. V.

Leuprolide [dLeu(6), NHEt(10)]GnRH, a potent gonadotropin-releasing hormone (GnRH) agonist, is used in a wide variety of hormone-related diseases like cancer and endometriosis. In this report, the conformational behaviour of Leuprolide and its linear synthetic analogues, namely [Tyr(5)(OMe), dLeu(6), Aze(9), NHEt(10)]GnRH (1) and [Tyr(5)(OMe), dLeu(6), NHEt(10)]GnRH (2) have been studied in DMSO and H(2)O solutions by means of 2D nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) simulations. The aim was to identify the conformational requirements of GnRH analogues for agonistic activity. This approach is of value as no crystallographic data are available for the GnRH receptor (G protein-coupled receptor, GPCR). The NOE data indicate the existence of a beta-turn type I in the 2-5 segments of Leuprolide and its linear analogues in the case of using DMSO-d(6) as solvent, whereas a beta-turn type II in the 3-6 segments is indicated using D(2)O as solvent. The final structures fulfil the conformational requirements that are known, in the literature, to play a significant role in receptor recognition and activation. Finally, the linear analogues (1) and (2) are biologically active when tested against the human breast cancer cell line, MCF-7.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών και Τεχνολογιών. Τμήμα Βιολογικών Εφαρμογών και Τεχνολογιών
Keywords: gonadotropin-releasing hormone (gnrh),leuprolide,nuclear magnetic resonance,bioactive conformation,molecular dynamics,gonadotropin-releasing-hormone,allergic encephalomyelitis eae,altered peptide ligands,breast-cancer-cells,receptor-binding,mo
ISSN: 0939-4451
Link: <Go to ISI>://000283502900006
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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