BACKGROUND AND PURPOSE: Drug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor-binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor-binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. EXPERIMENTAL APPROACH: A novel radioligand-binding competition association assay was developed and optimized for the human GnRH receptor with the use of a radiolabelled peptide agonist, [(125) I]-triptorelin. In addition to radioligand-binding studies, a homogeneous time-resolved FRET Tag-lite™ method was developed as an alternative assay for the same purpose. KEY RESULTS: Two novel competition association assays were successfully developed and applied to determine the kinetic receptor-binding characteristics of 12 high-affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). CONCLUSIONS AND IMPLICATIONS: Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor.
BACKGROUND AND PURPOSE: Drug-target residence time is an important, yet often overlooked, parameter in drug discovery. Multiple studies have proposed an increased residence time to be beneficial for improved drug efficacy and/or longer duration of action. Currently, there are many drugs on the market targeting the gonadotropin-releasing hormone (GnRH) receptor for the treatment of hormone-dependent diseases. Surprisingly, the kinetic receptor-binding parameters of these analogues have not yet been reported. Therefore, this project focused on determining the receptor-binding kinetics of 12 GnRH peptide agonists, including many marketed drugs. EXPERIMENTAL APPROACH: A novel radioligand-binding competition association assay was developed and optimized for the humanGnRH receptor with the use of a radiolabelled peptide agonist, [(125) I]-triptorelin. In addition to radioligand-binding studies, a homogeneous time-resolved FRET Tag-lite™ method was developed as an alternative assay for the same purpose. KEY RESULTS: Two novel competition association assays were successfully developed and applied to determine the kinetic receptor-binding characteristics of 12 high-affinity GnRH peptide agonists. Results obtained from both methods were highly correlated. Interestingly, the binding kinetics of the peptide agonists were more divergent than their affinities with residence times ranging from 5.6 min (goserelin) to 125 min (deslorelin). CONCLUSIONS AND IMPLICATIONS: Our research provides new insights by incorporating kinetic, next to equilibrium, binding parameters in current research and development that can potentially improve future drug discovery targeting the GnRH receptor.
Authors: Indira Nederpelt; Victoria Georgi; Felix Schiele; Katrin Nowak-Reppel; Amaury E Fernández-Montalván; Adriaan P IJzerman; Laura H Heitman Journal: Br J Pharmacol Date: 2015-11-04 Impact factor: 8.739
Authors: Ann Packeu; Jean-Paul De Backer; Isabelle Van Liefde; Patrick M L Vanderheyden; Georges Vauquelin Journal: Biochem Pharmacol Date: 2008-03-14 Impact factor: 5.858
Authors: Robert P Millar; Zhi-Liang Lu; Adam J Pawson; Colleen A Flanagan; Kevin Morgan; Stuart R Maudsley Journal: Endocr Rev Date: 2004-04 Impact factor: 19.871
Authors: Indira Nederpelt; Victoria Georgi; Felix Schiele; Katrin Nowak-Reppel; Amaury E Fernández-Montalván; Adriaan P IJzerman; Laura H Heitman Journal: Br J Pharmacol Date: 2015-11-04 Impact factor: 8.739
Authors: Wilhelmus E A de Witte; Joost W Versfelt; Maria Kuzikov; Solene Rolland; Victoria Georgi; Philip Gribbon; Sheraz Gul; Dymphy Huntjens; Piet Hein van der Graaf; Meindert Danhof; Amaury Fernández-Montalván; Gesa Witt; Elizabeth C M de Lange Journal: Br J Pharmacol Date: 2018-09-21 Impact factor: 8.739
Authors: Reggie Bosma; Leigh A Stoddart; Victoria Georgi; Monica Bouzo-Lorenzo; Nick Bushby; Loretta Inkoom; Michael J Waring; Stephen J Briddon; Henry F Vischer; Robert J Sheppard; Amaury Fernández-Montalván; Stephen J Hill; Rob Leurs Journal: Sci Rep Date: 2019-05-27 Impact factor: 4.379