The Chemical Biology group is a new established researchgroup within the department BME. Prof.dr.ir. Luc Brunsveld which is started in 2008.
The research deals with chemical biology approaches to study protein-protein interactions. Two general lines are being followed: 1) Supramolecular Architectures are being pursued as instruments to modulate protein-protein interactions and 2) the Nuclear Receptor – Cofactor interaction is being targeted as a model ‘drugable’ protein-protein interaction.
1) Supramolecular Architectures.
Supramolecular chemistry deals with molecular architectures that are assembled by the reversible interaction of two or more chemical species via non-covalent intermolecular forces. Research in supramolecular chemistry has moved from the investigations of the basis of molecular recognition all the way to control and utilization of self organization by design. In particular in the fields of material science, nanoscience, and nanotechnology designed supramolecular systems have proven to provide successful entries in modulating and controlling materials properties and functions. In biological systems all intermolecular and most intramolecular interactions are supramolecular. In contrast to the application of self-organization for the design and development of functional (nano)materials, supramolecular chemistry has rarely been applied to study and modulate biological phenomena. We aim to combine synthetic supramolecular architectures with biology to provide entries for studying, influencing and targeting biological phenomena.
1a) Supramolecular chemistry utilizes reversible noncovalent interactions to assemble molecules into multimolecular complexes. Supramolecular architectures are conformational unique and can be modulated with external elements such as light, temperature, pH or ligands. We are investigating supramolecular architectures as modulators of protein-protein interactions. By modification of proteins with supramolecular elements, the localization and interaction partners of the protein can be controlled with supramolecular stimuli.
1b) We also design supramolecular system that self-organize as multivalent scaffolds for interactions with cells. We develop multivalent systems with the unique ability to accommodate to the receptors in situ using the advantages of supramolecular architectures. We use disc shaped molecules with a N-N’-diacylated 2,2'-bipyridine-3,3'-diamine-scaffold which form helical supramolecular architectures in water. These molecules are functionalized with ligands binding to e.g. viruses or bacteria
2) The Nuclear Receptor – Cofactor Interaction
Nuclear receptors (NRs) are multi-domain ligand-modulated transcription factors that act by targeting chromatin-modifying complexes and the transcription machinery to their specific response elements on the DNA. The importance of these NR protein-protein interactions are in contrast to the very limited availability of molecular knowledge on these protein-protein interactions. NRs are validated drug targets as their functioning can be modulated by the type of ligand bound, i.e. via modulation of the protein-protein interactions. The molecular understanding of the influence of the ligand on the structure of the NR, beyond the rather well characterized Ligand Binding Domain (LBD) of the NRs, and on the protein-protein interactions is basically missing.
Our research deals with chemical biology approaches to investigate the NR-cofactor interaction. In this our focus is to answer the question how this interaction is regulated on a molecular level. To answer this question we follow several different approaches. We investigate the influence of post-translational modifications on the NR – cofactor binding, and aim to synthesize the NR via protein semi-synthesis. We investigate the cellular localization of NRs and Cofactors under the influence of specific regulating compounds and we design special inhibitors for the NR – cofactor interaction.