title: In vivo properties of an anti-GnRH Spiegelmer: an example of an oligonucleotide-based therapeutic substance class.
abstract: Spiegelmers are high-affinity l-enantiomeric oligonucleotide ligands that display high resistance to enzymatic degradation compared with d-oligonucleotides. The target binding properties of Spiegelmers can be designed by an in vitro-selection process starting from a random pool of oligonucleotides. Applying this method, a Spiegelmer with high affinity (K(D) = 20 nM) for the peptide hormone, gonadotropin-releasing hormone (GnRH) was isolated. The Spiegelmer acts as an antagonist to GnRH in Chinese hamster ovary cells stably expressing the human GnRH receptor, and its activity is unchanged by linking to 40-kDa polyethylene glycol. In a castrated rat model the Spiegelmer further demonstrated strong GnRH antagonist activity, which is more pronounced and persists longer with the polyethylene glycol-linked derivative. Furthermore, in rabbits the anti-GnRH Spiegelmer was shown to have a very low, possibly negligible immunogenic potential. These studies suggest that Spiegelmers could be of substantial interest in the development of new pharmaceutical approaches against GnRH and other targets.
authors.affiliation: NOXXON Pharma AG, Gustav-Meyer-Allee 25, 13355 Berlin, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Wlotzka
authors.forename: Susanne
authors.initials: S
authors.lastname: Leva
authors.forename: Bernd
authors.initials: B
authors.lastname: Eschgfäller
authors.forename: Jens
authors.initials: J
authors.lastname: Burmeister
authors.forename: Frank
authors.initials: F
authors.lastname: Kleinjung
authors.forename: Christine
authors.initials: C
authors.lastname: Kaduk
authors.forename: Peter
authors.initials: P
authors.lastname: Muhn
authors.forename: Holger
authors.initials: H
authors.lastname: Hess-Stumpp
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D017931:DNA Primers; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D008297:Male; D009841:Oligonucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats
chemical_list: D017931:DNA Primers; D009841:Oligonucleotides; D007987:Gonadotropin-Releasing Hormone