Universiteit Leiden

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Proefschrift

Activity-based protein profiling in drug discovery

In the last decades, activity-based protein profiling (ABPP) has emerged as a powerful chemical tool that may aid the ever-challenging drug discovery process.

Auteur
Esbroeck, A.C.M. van
Datum
28 mei 2019
Links
Thesis in Leiden Repository

In the last decades, activity-based protein profiling (ABPP) has emerged as a powerful chemical tool that may aid the ever-challenging drug discovery process. In this thesis ABPP is explored as a versatile tool in drug discovery and cell biology.ABPP enabled rapid assessment of clinical samples from patients suffering from cardiac ischemia, thereby giving insight into the serine hydrolase activity profile of these patients. The identification of molecular role players may lead to the discovery of novel therapeutic targets or biomarkers. In addition, ABPP can provide insight in a drug’s interaction landscape, by enabling target engagement studies and inhibitor selectivity profiling. This was demonstrated by the identification of multiple off targets of the experimental drug BIA 10-2474 that caused severe neurological symptoms in a phase I clinical trial. In zebrafish larvae, the ABPP methodology enabled in vivo selectivity profiling and in addition served as a powerful tool to map the kinase and serine hydrolase landscape throughout embryonic development. Lastly, combining ABPP with other biochemical techniques including CRISPR/Cas9 technology and lipidomics, can provide new insights in cellular biology, which was showcased by the identification of ABHD6 as a diacylglycerol-lipase in a cellular model of neuronal differentiation.

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