Development of Proteolysis Targeting Chimeras (PROTACs). PROTACs are reagents that recruit a protein of interest to a specific ubiquitin (Ub) E3 ligase, inducing its ubiquitination and subsequent destruction by the 26S proteasome. In other words, whereas classical drug discovery either focuses on receptor ligands and enzyme inhibitors, the PROTAC strategy has the additional advantage of specifically removing targets altogether. Currently, we are developing PROTACs reagents targeting different proteins.
Development of ISG15-based probes. ISG15 is a ubiquitin-like protein and can be covalently added to cytoplasmic and nuclear proteins (ISGylation). Besides ISGylation, ISG15 also has anti-viral activity. It is very interesting to identify both the intracellular and extracellular roles of ISG15. In order to do this, we aim to develop various probes based on ISG15.
I did my PhD in Herman Overkleeft’s group in Department of Bio-organic Synthesis at Leiden Institute of Chemistry. My work focused on the development of subunit-specific inhibitors and activity-based probes for human constitutive proteasomes and immunoproteasomes. After my PhD, I joined Huib Ovaa’s group as a post-doc. Part of my research is to develop novel proteasome inhibitors as well as novel reagents which can manipulate the Ubiquitin Proteasome System. Another part of my research focuses on the development of reagents based on ISG15.
Structure-based design of β5c selective inhibitors of human constitutive proteasomes
Bo-Tao Xin, Gerjan de Bruin, Eva M. Huber et al.
J. Med. Chem., 2016, 7177-7187.
Incorporation of the constrained peptidomimetic,
5-methylpyridin-2-one into peptide vinyl sulfones and peptide epoxyketone is detrimental for proteasome
Bo-Tao Xin, Gerjan de Bruin, Jan-Willem et al.
Eur. J. Org. Chem., 2016, 1132-1144.
Exploring dual electrophiles in peptide-based
proteasome inhibitors: carbonyls and expoxides
Bo-Tao Xin, Gerjan de Bruin, Martijn Verdoes et al.
Org. Biomol. Chem., 2014, 5710-5718.