S- and C-glycopeptide derivatives of an LH-RH agonist.
The S- and C-glycosylated nonapeptides 1 and 2 were synthesized as analogs of the non-glycosylated LH-RH agonist buserelin (pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro-NHEt) by segment condensation in solution. 1 and 2 differ from this peptide in the amino acid in position 6. In the first case (1), D-serine (tBu) is substituted by D-cysteine carrying a rhamnosyl residue, in the second case (2) D-alanine carrying a galactosyl moiety bound as C-glycoside is incorporated. The bioactivity of both glycopeptides as fertility drugs was determined from the dose dependent LH release in male rats. Additionally, in female rats the ovulation rate was assessed. As a result the analog 1 exhibits a similar biological activity as buserelin while analog 2 shows about 25% of this potency. Compared to buserelin the solubility of the analogs 1 and 2 in aqueous buffer is improved by more than two orders of magnitude due to the carbohydrate moieties.
Michael
K
K
Institute for Organic Chemistry and Biochemistry, Technical University of Munich, Garching, Germany.
Wittmann
V
V
König
W
W
Sandow
J
J
Kessler
H
H
D000409:Alanine / Q000737:chemistry; D000818:Animals; D002064:Buserelin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D002241:Carbohydrates / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D005260:Female; D006020:Glycopeptides / Q000138:chemical synthesis*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D007986:Luteinizing Hormone / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010060:Ovulation / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
D002241:Carbohydrates; D006020:Glycopeptides; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D003545:Cysteine; D000409:Alanine; D002064:Buserelin