Prize winners AIMMS Annual Meeting 2016
The prize winners and runner up of the competitions at the AIMMS Annual Meeting Thursday 14 April 2016 are introduced below.
05/11/2016 | 6:05 PM
PhD competition winner
Stefan Dekker, PhD student at the Molecular Toxicology group under supervision of dr Jan Commandeur and prof. Nico Vermeulen on an IMI MIP-DILI project, received an award for his oral PhD presentation, “Different reactive metabolites of nevirapine require distinct glutathione S-transferase isoforms for bio-inactivation”. Nevirapine is a reverse transcriptase inhibitor which can cause severe hepatotoxicity in 3% of the patients taking this drug. The covalently bound metabolites of nevirapine cause an immune response. Dekker researched the risk factors of polymorphisms in glutathione S-transferases and their ability to catalyze GSH-conjugation. This lead to the discovery of key roles of the GSTP1, GSTM1, GSTA1 and GSTA3 alleles in the hepatotoxicity of nevirapine. This study shows that genetic polymorphisms of drug-metabolizing enzymes can play a role in the idiosyncracy of nevirapine hepatotoxicity.
PhD competition runner up
Reggie Bosma, PhD student at the Medicinal Chemistry research group, was awarded the “Runner-up Award” for his oral presentation, entitled ‘Long residence antihistamines and implications for drug discovery’ Bosma presented his work on the relevance of drug-receptor residence time as a way to steer drug development. Early evaluation of residence time as selection criterion in drug discovery is widely seen as an innovative way to optimize the drug efficacy in vivo.
Bosma presented a new assay in which activation of the H1 receptor in living cells was measured by real-time monitoring of the interaction between the receptor and β-arrestin2 using bioluminescence-resonance energy transfer (BRET). Moreover, the BRET-based monitoring of this interaction could be used to determine the residence time of a series of H1 antagonists. The new methodology is non-radioactive, is performed real time on living cells and allows a much higher throughput than radioligand binding experiments. This work is part of Bosma’s PhD project under supervision of Dr. Henry Vischer and Prof. dr. Rob Leurs and is part of the European Innovative Medicine Initiative consortium “Kinetics for Drug Discovery (K4DD)”.
Poster prize winners (in alphabetical order)
Timo De Groof, PhD student at the Medicinal Chemistry group under supervision of Prof. Martine Smit, received an award for his poster “Identification and characterization of viral GPCR-targeting nanobodies”. The human cytomegalovirus (HCMV) is believed to play a role in the progression of glioblastoma and encodes four G protein-coupled receptors. To further investigate the oncomodulatory role of these receptors in glioblastoma, De Groof develops nanobodies targeting these viral receptors. These single-domain antibody fragments, unique to Camelids, are being identified in house by means of a newly established nanobody platform. The success of this platform is shown by the identification of different classes of nanobodies targeting the HCMV-encoded chemokine receptor US28. These nanobodies will be further characterized and identification of nanobodies targeting the other viral receptors, using this new platform, is ongoing within the framework of Prof. Martine Smit’s NWO VICI project on the contribution of viral receptor proteins to brain tumors.
Tamara Mocking, PhD student at the division of Medicinal Chemistry, has received an award for her poster entitled ‘A BRET-based kinetic ligand-receptor binding assay for the histamine H3 receptor’. In drug discovery many drug candidates do not reach the market due to lack of in vivo efficacy. Many of these drug are selected based on their affinity while residence time, i.e. the time a drug stays bound to the receptor might better reflect in vivo efficacy. Mocking developed a novel method to measure ligand-receptor binding kinetics utilizing bioluminescence resonance energy transfer (BRET) with a nanoluciferase-tagged histamine H3 receptor in combination with a fluorescently labeled ligand to measure the binding of the ligand to the receptor in real time. This work is part of Mocking’s PhD project under supervision of Dr. Henry Vischer and Prof. Dr. Rob Leurs and is funded by a NWO Toppunt grant.
Yongjie Zhang, PhD student at the Molecular Toxicology group under supervision of dr Jan Commandeur and Prof. Nico Vermeulen on a CSC grant , received an award for his poster “Characterization of human cytochrome P450 mediated bioactivation of amodiaquine and its major metabolite N-desethylamodiaquine”. Amodiaquine (AQ) is widely used in the endemic area of Africa and Asia. However, due to its idiosyncratic toxicity, prescription of this drug is limited in a lot of countries. Zhang studied the toxicity of AQ and its principal metabolite N-desethylamodiaquine (DEAQ). He focused on the enzyme kinetics and involvement of individual P450s in the bioactivation of AQ and DEAQ. In the study, he first found that high- and low-affinity enzymes were involved. Then, he identified their contribution to the bioactivation. Lastly, he confirmed the involvement of these enzymes by isozyme inhibition experiment.
To read the full report on the AIMMS Annual Meeting 2016, click here.