Molecular Pharmacology (Drug Discovery & Target Finding)

Research topics

• Novel concepts in Drug Discovery
  To study ligand (drug) interactions with receptors, signal transduction events, and novel concepts like ligand-independent signaling and receptor dimerization, our molecular receptor pharmacologists use molecular biology, pharmacology, and innovative imaging and biophysical approaches. These studies aim on elucidating the role of receptors in health and disease, and ultimately to validate their potential as future target for pharmaceutical intervention.

• Network-based Drug Discovery to find new drug targets
  In order to fully understand the key role of GPCRs in pathological signaling, a Systems Biology approach is required to map the key signaling events and components. The role of (viral) GPCRs in pathology (cancer, inflammatory disease) is investigated using genome- and proteome wide analyses. These studies unveil the intricate organisation and interplay of signaling pathways involved. Besides identification of new drug targets, this approach will also direct in vivo studies to examine and modulate the clinically relevant GPCR-induced signaling pathways.

• Human and viral chemokine receptors as novel targets for therapeutic intervention of cancer
  The cloning of the human genome resulted in the identification of many new drug targets, including new (orphan) GPCRs, histamine (H4) and chemokine (CXCR7) receptors. Within the ‘Receptor Structure Function’ research group we are examining the role of these novel receptors in inflammation and cancer using in vitro (cell-based signaling assays) and in vivo (xenograft mouse) model systems. Moreover, also genomes of herpesviruses contain genes encoding GPCRs, which show homology to chemokine receptors. Interestingly, these viral chemokine receptors display oncogenic properties and induce tumor formation in vivo. As such, these viral receptors may play a role in cancer after viral infection and can be considered as novel drug targets.

US28 a viral-encoded oncogenic GPCR (molecular mechanisms of human disease)under supervision of Prof. dr. Martine Smit
G protein coupled receptors (GPCRs) are cell-surface proteins that play a key role in cellular communication. They respond to a range of diverse external stimuli, activating various signalling pathways, and regulating a large number of physiological processes. Hence, strict control of GPCR-mediated signal transduction is essential for the proper functioning of cells.

We study the oncogenic properties of a viral (Human cytomegalo virus, HCMV) encoded GPCR, US28. In recent years it has become clear that some viruses carry GPCR genes, probably derived from the genomes of the host cells, most of which encode receptors with constitutive (stimulus-independent) activity. Upon infection, these viral GPCRs hijack the host cell’s signalling machinery, which may result in pathogenesis. Indeed, the expression of US28 results in oncogenic responses, such as increased DNA synthesis and the secretion of Vascular Epidermal Growth Factor (VEGF).


Figure: viral-GPCR expression after viral infection. Background; foci formation as a consequence of US28 expression (middle plate).

We are currently investigating the US28-induced alterations of the host cell’s signal transduction, which may be responsible for this pathology. Using microarray analysis (to detect changes in overall cellular mRNA levels), kinome analysis (to detect activity or inhibition of kinases), several signalling pathways have been shown to be modified in the presence and activity of US28. Apparently, US28 influences host-cell signalling through interaction with signalling proteins that determine whether the cell will proliferate or whether the cell’s death programme will be induced. If we can isolate and characterize the components of the signalling complexes associated with US28 (immunoprecipitation followed by Mass Spectroscopy) and the down-regulation of signalling (specific inhibitors or siRNA approaches), this will allow the oncogenic properties of US28 to be further determined. Finally, using the small compound libraries available in the group, we aim to inhibit US28-induced oncogenesis. These molecules could potentially be used in the treatment of viral-GPCR-mediated pathology.