Project description
Treating the world’s expanding waistlines
Sedentary lifestyles, increased screen time, overnutrition and obesity are all characteristics of metabolic syndrome (MetS), which is increasing to epidemic proportions. MetS is associated with an increase in cardiovascular disease risk and type 2 diabetes mellitus. Treatment options for MetS-associated comorbidities, including dyslipidaemia, diabetes, obesity, and fatty-liver disease, are far from optimal. The EU-funded CHANCE project will address this challenge by capitalising on the high-resolution 3D structure of IDOL (inducible degrader of the low-density lipoprotein receptor), which can modulate cholesterol levels. The project will identify and validate small-molecule IDOL inhibitors by using a structure-guided development pipeline that combines an established virtual ligand docking protocol, and in vitro and in vivo validation.
Objective
The prevalence of the MetS and associated co-morbidities including cardiovascular disease has reached epidemic proportions in the developed and developing world. The cost of treating these conditions represents a substantial part of current European healthcare expenditure, and despite recent advances, treatments for MetS-associated lipid disorders are far from optimal; mainstay lipid-lowering treatments (e.g. statins) reduce cardiovascular risk by only ~30%, and recently-introduced PCSK9 inhibitors are promising, but prohibitively expensive. Moreover, epidemiologic and genetic evidence suggests that these treatment modalities are associated with a significant increase in the risk for development of diabetes. Treatments for other MetS-associated comorbidities, including dyslipidemia, diabetes, obesity, and fatty-liver disease are far from optimal or lacking. In ERC-CoG UNICOM we discovered that genetic inhibition of the E3-ubiquitin ligase IDOL protects mice from the detrimental development of multiple MetS-associated comorbidities. We therefore propose IDOL inhibition as a novel therapeutic strategy to concomitantly target multiple metabolic co-morbidities. However, absence of a high resolution IDOL structure has hampered structure-guided development of inhibitors. In CHANCE, we will capitalize on the high resolution 3D structure of IDOL that we recently obtained. Using this unique structure we aim to identify and validate small-molecule IDOL inhibitors by using a structure-guided development pipeline that combines an established virtual ligand docking protocol, and in vitro and in vivo validation. Lead hits will be used for development of a business and IP strategy to ensure the sustainable development of IDOL inhibitors for treating the MetS.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosis
- medical and health sciencesclinical medicineendocrinologydiabetes
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health scienceshealth sciencesnutritionobesity
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Programme(s)
Funding Scheme
ERC-POC-LS - ERC Proof of Concept Lump Sum PilotHost institution
1105AZ Amsterdam
Netherlands