Voll, Andreas Markus (2023)
Design, synthesis and biological evaluation of novel FKBP51 ligands.
Technische Universität Darmstadt
doi: 10.26083/tuprints-00017949
Dissertation, Erstveröffentlichung, Verlagsversion
Kurzbeschreibung (Abstract)
The FK506-binding protein 51 (FKBP51) has emerged as an attractive new drug target for mood disorders, obesity and chronic pain. The most advanced FKBP51 ligands of the SAFit class are highly selective against the anti-target FKBP52, but only poorly discriminate against the homologs FKBP12 and FKBP12.6. To improve SAFit-like compounds we employed a structure-based approach: Envisioning enhanced properties of macrocycles like increased oral bioavailability, metabolic stability and selectivity compared to the linear SAFit-construct, we designed and synthesized FKBP-binding macrocycles. These macrocycles were synthesized via ring-closing-metathesis and a solid-phase assisted approach. Surprisingly, we observed that many of these macrocyclic analogs have a novel high preference for FKBP51 over FKBP12 and FKBP12.6 and that they bind with a new binding mode featuring a transient conformation that is disfavored for the small FKBPs. These findings represent the structural basis for enhanced selectivity and a new chemical scaffold for selective FKBP51 ligands. Furthermore, we present the rational design and synthesis of novel A and B ring derivatives of SAFit1 (an essential building block of SAFit-ligands). Reducing the size of SAFit to explore the necessary interactions and subsequently combining the most favorable moieties resulted in novel diaza-chalcone derivatives. These compounds reached similar FKBP51 selectivity and affinity in comparison to SAFit1 and most importantly displayed a reduced weight by up to 132 g/mol. Additionally, a compound series of A/B ring-analogs was synthesized by Click reaction, which displayed a new preference for FKBP12.6 over FKBP12. This may offer new possibilities to alter FKBP selectivities.
| Typ des Eintrags: | Dissertation | ||||
|---|---|---|---|---|---|
| Erschienen: | 2023 | ||||
| Autor(en): | Voll, Andreas Markus | ||||
| Art des Eintrags: | Erstveröffentlichung | ||||
| Titel: | Design, synthesis and biological evaluation of novel FKBP51 ligands | ||||
| Sprache: | Englisch | ||||
| Referenten: | Hausch, Prof. Dr. Felix ; Schmidt, Prof. Dr. Boris | ||||
| Publikationsjahr: | 2023 | ||||
| Ort: | Darmstadt | ||||
| Kollation: | VII, 322 Seiten | ||||
| Datum der mündlichen Prüfung: | 19 April 2021 | ||||
| DOI: | 10.26083/tuprints-00017949 | ||||
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/17949 | ||||
| Kurzbeschreibung (Abstract): | The FK506-binding protein 51 (FKBP51) has emerged as an attractive new drug target for mood disorders, obesity and chronic pain. The most advanced FKBP51 ligands of the SAFit class are highly selective against the anti-target FKBP52, but only poorly discriminate against the homologs FKBP12 and FKBP12.6. To improve SAFit-like compounds we employed a structure-based approach: Envisioning enhanced properties of macrocycles like increased oral bioavailability, metabolic stability and selectivity compared to the linear SAFit-construct, we designed and synthesized FKBP-binding macrocycles. These macrocycles were synthesized via ring-closing-metathesis and a solid-phase assisted approach. Surprisingly, we observed that many of these macrocyclic analogs have a novel high preference for FKBP51 over FKBP12 and FKBP12.6 and that they bind with a new binding mode featuring a transient conformation that is disfavored for the small FKBPs. These findings represent the structural basis for enhanced selectivity and a new chemical scaffold for selective FKBP51 ligands. Furthermore, we present the rational design and synthesis of novel A and B ring derivatives of SAFit1 (an essential building block of SAFit-ligands). Reducing the size of SAFit to explore the necessary interactions and subsequently combining the most favorable moieties resulted in novel diaza-chalcone derivatives. These compounds reached similar FKBP51 selectivity and affinity in comparison to SAFit1 and most importantly displayed a reduced weight by up to 132 g/mol. Additionally, a compound series of A/B ring-analogs was synthesized by Click reaction, which displayed a new preference for FKBP12.6 over FKBP12. This may offer new possibilities to alter FKBP selectivities. |
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| Status: | Verlagsversion | ||||
| URN: | urn:nbn:de:tuda-tuprints-179499 | ||||
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie | ||||
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie |
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| Hinterlegungsdatum: | 12 Mai 2023 12:06 | ||||
| Letzte Änderung: | 15 Mai 2023 05:13 | ||||
| PPN: | |||||
| Referenten: | Hausch, Prof. Dr. Felix ; Schmidt, Prof. Dr. Boris | ||||
| Datum der mündlichen Prüfung / Verteidigung / mdl. Prüfung: | 19 April 2021 | ||||
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