Synthesis of natural product-derived and inspired compound collections
Natural products and their derivatives have been and remain a rich source of bioactive compounds. Most chemical modifications around a natural product scaffold are typically carried out at the periphery, at preexisting reactive sites. However the great potential that lies in the modification of the core scaffold, as well as the fusion of diverse natural product scaffolds, has been poorly explored. My group aims to create new biologically relevant scaffolds comprising elements of different natural product classes, initially focusing on sterols. These will be employed in phenotypic and target based screens to assess their potential as new leads or tool compounds in drug discovery.
Phenotypic screening
Phenotypic screening is a powerful tool to identify a compound’s bioactivity, as it allows the simultaneous screening of many targets associated with a given phenotype. A good phenotypic screen provides a more disease-relevant model as well as selecting compounds that are cell permeable. My group is interested in using such screens to identify new small molecules that can interfere with cholesterol biosynthesis, metabolism and trafficking, with applications in atherosclerosis, lysosomal storage disorders and cancer.
Target identification of natural and non-natural small molecules
Advances in mass spectrometry-based proteomic approaches have resulted in the development of several complimentary approaches for the identification of small molecule-protein interactions. Our group uses covalent and non-covalent pull-downs, as well as thermal proteome profiling, to identify the targets of naturally occurring sterols as well as hit compounds that we identify in our phenotypic screens. We subsequently validate the identified targets using biophysical and cell biological approaches.