Spiranic compounds as novel AMPK paradoxical inhibitors: can we derive new mechanistic
[EN] 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...
| Authors: | , , , , , , , , , , , , , |
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| Format: | article |
| Publication Date: | 2026 |
| Country: | España |
| Institution: | Universitat Politècnica de València (UPV) |
| Repository: | RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia |
| Language: | English |
| OAI Identifier: | oai:dnet:riunet______::6fca767c1e08595504d76e8e60304354 |
| Online Access: | https://riunet.upv.es/handle/10251/235054 |
| Access Level: | Open access |
| Keyword: | AMPK Mixed-type inhibition Vasodilation Endothelial function Protein dynamics Closed A -loop Paradoxical inhibitor |
| Summary: | [EN] 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 alpha 1(31 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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