The inverse electron demand Diels-Alder (IEDDA) pyridazine elimination emerged in 2013 as a new bioorthogonal reaction and constitutes a prime example of what is now known as dissociative... Show moreThe inverse electron demand Diels-Alder (IEDDA) pyridazine elimination emerged in 2013 as a new bioorthogonal reaction and constitutes a prime example of what is now known as dissociative bioorthogonal chemistry. The research described in this Thesis aims to develop synthetic strategies which enable the IEDDA pyridazine elimination to be applied as a versatile toolbox in chemical biology studies. More specifically, it entails modification of antigenic (MHC-I) peptides and (CD1d) glycolipids with a trans-cyclooctene (TCO) moiety to allow chemical control over the recognition of these biomolecules by immune cells. Synthetic advances which encompass the entire scope of the IEDDA pyridazine elimination are additionally described. Show less
Cytotoxic T-cells (CTLs) are involved in the clearance of viruses and killing of tumor cells. The capacity of these killer cells to clear viruses and kill tumor cells can be harbored by the... Show moreCytotoxic T-cells (CTLs) are involved in the clearance of viruses and killing of tumor cells. The capacity of these killer cells to clear viruses and kill tumor cells can be harbored by the creation of vaccines. Improving understanding of T-cell activation and the possibility to understand, influence or even have control over this process might lead to better anti-cancer vaccines. Chemical tools can be a good addition to fill in the gaps of knowledge about T-cell activation. Show less
Phosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions. A prime example of a... Show morePhosphorylation affects all four major biomolecules – proteins, lipids, carbohydrates and nucleic acids – and plays a pivotal role in the most fundamental cellular functions. A prime example of a PTM that caught a lot of scientific interest is adenosine diphosphate ribosylation (ADP-ribosylation), carried out by the PARP family of enzymes. ADP-ribosylation is an indirect form of (pyro)phosphorylation, where a monomer or polymer of ADPr is attached to an acceptor protein. The process of ADP-ribosylation has been linked to DNA damage repair, telomere maintenance and regulation of apoptosis, highlighting it of biomedical importance, most notably in relation to cancer therapy and inflammatory disorders. Well-defined phosphorylated molecular tools have already proven to be effective at elucidating the molecular mechanisms behind both normal and pathological cell function. However, the natural pyrophosphate group is inherently susceptibility to hydrolysis, trans-esterification and enzymatic cleavage. This property limits their use through possible premature degradation or restricted synthetic accessibility. The research described in this thesis focuses on the development of new molecular tools, primarily intended to facilitate the study of adenosine diphosphate ribosylation. In this context new reagents and methodologies have been developed for the synthesis of stabilized pyrophosphorylated bioisosteres. Show less
Engelsma, S.B.; Ende, T.C. van den; Overkleeft, H.S.; Marel, G.A. van der; Filippov, D.V. 2018
