Nuclear receptor ligands from Arctic marine organisms; Bioprospecting, structure, synthesis and evaluation as drug to treat metabolic syndro

Obesity is a major cause of diseases that can increase morbidity and mortality. Obesity leads to metabolic disorders (MD) including hyperglycemia and dyslipidemia. Current treatment includes ligands for the metabolite-activated transcription factors (PPAR s, LXRs). Despite their beneficial effects these drugs also have adverse effects such as weight gain and fluid retentions. The adverse effects are assumed to be drug related, and not target related. These drugs also influence on inflammation, and more sel ective agonists is desirable This shift in focus on new PPAR ligands is due to the fact that sub-lethal inflammation correlate strongly with obesity, and that a sedentary life and obesity also profoundly shift intestinal microflora, and induce inflammatio n. This project represents a new approach for discovering drug candidates to MD, initiated by bioassay guided screening distinguished by: 1) Bioprospecting on a material that so far has an ignorable exploration rate for the biological activity sought.. 2 ) The primary screening will be based on cell assays that, compared to biochemical assays, reduce the number of false positive hits. 3) Positive fractions will show comparable dose-response on reporter gene activity in two cell types. 4) Drug candidates w ill demonstrate selectivity towards recruitment of co-activators to the transcription complex. 5) A kinase assay based screening system that will pick up biological activities that block phopsphorylation of S273 in PPARg, independently of receptor agonism . Positive hits from the screening will be followed up by compound purification, structure analysis and synthesis, together with studies on the anti-diabetic potential utilising state-of-the-art approaches in cell, animal and human genetics, functional g enomics and proteomics, and physiological and pharmacological research tools. Before any publication, evaluation of any innovative potential of the molecules will be conducted together with our commercial partner.