Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.

Informazioni relative al progetto

ADIPOR

ID dell’accordo di sovvenzione: 647687

DOI

10.3030/647687

Progetto chiuso

Data della firma CE 26 Giugno 2015

Data di avvio 1 Luglio 2015

Data di completamento 31 Dicembre 2020

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 989 518,00

Contributo UE

€ 1 989 518,00

Coordinato da

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - ADIPOR (Molecular and structural pharmacology of adiponectin receptor: towards innovative treatments of obesity-related diseases.)

Periodo di rendicontazione: 2020-01-01 al 2020-12-31

Sintesi del contesto e degli obiettivi generali del progetto

Increased ceramide levels in obese individuals have been demonstrated to correlate with insulin resistance and type II diabetes. Adiponectin receptors (ADIPORs) are integral membrane proteins possessing potent antidiabetic actions, at least partly arbitrated to receptor-associated ceramidase activity, resulting in hydrolysis of ceramide to sphingosine and fatty acid. The recent crystal structures of two receptor subtypes, ADIPOR1 and ADIPOR2, revealed that their architecture but the molecular mechanisms of ADIPORs function were still obscure however.
The overall objectives of the project was to characterize how the adiponectin binding to the receptor ADIPORs leads to anti-diabetic, anti inflamatory and anti-proliferative actions using structural biology and pharmacology. Ultimately, this study will enable the development of treatment for obesity-related diseases such as type 2 diabetes, cardiovascular diseases ans cancer.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

This ERC grant focused on the molecular and structural pharmacology of adiponectin receptors (ADIPORs). ADIPORs are promising targets for ORD (T2D etc..) but, so far, drug discovery programs have failed, most likely due to the lack of structural and functional knowledge on this membrane protein and to the absence of an efficient technology to screen for molecules that can modify their activity.
During our ERC ADIPOR, we have discovered a novel enzymatic activity of adiponectin receptors as well as their structural identity/relationships with alkaline ceramidases (ACER3) (Nature and Nature comm papers). ACER3 has been implicated in human diseases (Leukodystrophy E33G mutant and AML cancers).
Those two enzymes modulate the level of ceramide, a key bioactive lipid implicated in many pathophysiological conditions (insulin sensitivity, apoptosis).
Importantly, we have succeeded in developing an innovative biophysical assay to monitor the ceramidase enzymatic activity in a high-throughput manner (IP protection undergoing with INSERM-transfert).

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

In conclusion of the action, the biochemical and structural data obtained during this grant demonstrate that ADIPORs are enzymes. Since insulin resistance and type 2 diabetes correlate with increased levels of ceramides and reduced expression of ADIPORs, this study may facilitate the development of new therapeutic approaches to treating obesity-related diseases by modifying the enzymatic activity of the ADIPORs. The three most significant achievements are the discovery of structures and enzymatic activities of Adiponectin receptors, the discovery of structures of AdipoRs analogs involved in human diseases and the development of key technologies to enable drug discovery to treat diseases involving ADIPORs and ceramidases.

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