GnRH binding RNA and DNA Spiegelmers: a novel approach toward GnRH antagonism.
Mirror-image oligonucleotide ligands (Spiegelmers) that bind to the pharmacologically relevant target gonadotropin-releasing hormone I (GnRH) with high affinity and high specificity have been identified using the Spiegelmer technology. GnRH is a decapeptide that plays an important role in mammalian reproduction and sexual maturation and is associated with several benign and malignant diseases. First, aptamers that bind to D-GnRH with dissociation constants of 50-100 nM were isolated out of RNA and DNA libraries. The respective enantiomers of the DNA and RNA aptamers were synthesized, and their binding to L-GnRH was shown. These Spiegelmers bind to L-GnRH with similar affinity to that of the corresponding aptamers that bind to D-GnRH. We further demonstrated dose-dependent inhibition of GnRH-induced Ca(2+) release in Chinese hamster ovary cells that were stably transfected with the human GnRH receptor.
Leva
Susanne
S
NOXXON Pharma AG, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany.
Lichte
Andrea
A
Burmeister
Jens
J
Muhn
Peter
P
Jahnke
Birgit
B
Fesser
Dirk
D
Erfurth
Jeannette
J
Burgstaller
Petra
P
Klussmann
Sven
S
D000818:Animals; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D017931:DNA Primers; D015723:Gene Library; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D009841:Oligonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
D017931:DNA Primers; D008024:Ligands; D009841:Oligonucleotides; D007987:Gonadotropin-Releasing Hormone