Spiranic compounds as novel AMPK paradoxical inhibitors: can we derive new mechanistic insights?
In this study, we synthesized and fully characterized spiranic compounds designed as conformationally restricted mimetics of A-769662 by means of crystallographic, spectroscopic, and computational methods. In vitro enzymatic assays and surface plasmon resonance experiments revealed a mixed-type inhi...
| Autores: | , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:dnet:digitalcsic_::03db19b33a0fdccb0503a85e25bc7927 |
| Acceso en línea: | http://hdl.handle.net/10261/430271 https://api.elsevier.com/content/abstract/scopus_id/105035495196 |
| Access Level: | acceso abierto |
| Palabra clave: | AMPK Closed A-loop Endothelial function Mixed-type inhibition Paradoxical inhibitor Protein dynamics Vasodilation |
| Sumario: | In this study, we synthesized and fully characterized spiranic compounds designed as conformationally restricted mimetics of A-769662 by means of crystallographic, spectroscopic, and computational methods. In vitro enzymatic assays and surface plasmon resonance experiments revealed a mixed-type inhibition mechanism. We developed a stable and equilibrated α1β1 AMPK model featuring the A-loop in a closed conformation, which was used to investigate alternative binding pockets beyond the canonical AMPK sites, namely type II-like pocket. The cell-based and tissue experiments further demonstrated that these compounds act as paradoxical inhibitors, since it enhances downstream signalling by increasing phosphorylation of ACC and eNOS, ultimately activating the AMPK-eNOS-NO pathway and inducing vasodilation in rat aorta. Altogether, our findings offer new insights into AMPK modulation and highlight the potential of spiranic scaffolds as tools for probing alternative regulatory mechanisms. |
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