Synthesis, Identification, and Chemoenzymatic Functionalisation of Inhibitors of Sterol Transport Proteins
Sterol transport proteins (STPs) are an important class of proteins responsible for intracellular sterol transport and lipid metabolism. They are crucial in the general cholesterol homeostasis, and their mis-regulation has been associated with lipid storage disorders, atherosclerosis, and a wide range of cancers. Despite their importance, very few STP inhibitors have been reported, often with little or no selectivity annotations, and the majority of these target a small fraction of STPs, highlighting a significant gap in the field.
To address this problem, a novel cholic-acid inspired compound collection of was synthesised through the combination of different compound library synthesis strategies. The cis-decalin AB-ring system as found in cholic acid was used as a “bait” for STPs and fused with other natural product scaffolds followed by various distortion reactions to create diverse compounds. Such compounds should bind STPs, hopefully with selectivity for one STP over another. Through biological screening, the complex and three-dimensional spirooxepinoindole was identified as general binder for STPs. Through careful optimisation of the scaffold the selectivity could be directed towards a single transporter, as showcased by the development of (−)-Asteroxin-1 as a potent and selective Aster-A inhibitor. (–)-Asteroxin-1 and its related compounds could be functionalised using enzymes achieving site-selectivity not easily accessible by classical chemical means.
The spirooxepinoindole scaffold has great potential in the development of new potent and selective modulators of STPs due its general binding to this class of protein. Additionally, the enzymatic functionalisation of active compounds provides an attractive alternative to general chemical methods.
Principal Supervisor:
Associate Professor Luca Laraia, DTU Chemistry
Co-supervisor:
Professor Mads H. Clausen, DTU Chemistry
Examiners:
Associate Professor Søren Kramer, DTU Chemistry
Professor Adam Nelson, University of Leeds, United Kingdom
Professor Thomas B. Poulsen, Aarhus University
Chairperson:
Dr. Laura Depta, DTU Chemistry
Zoom: https://dtudk.zoom.us/j/69870124145?pwd=vtD5C1zhAPL0FJqCpW37aj3kkdH8EB.1