Targeting Human Proteasomes: Substrates, Inhibitors and Prodrugs
Large parts of the research described in this Thesis aims at the development of oligopeptide-masked toxins and their in situ immunoproteasome-mediated activation.
- Maurits, E.
- 07 juli 2020
- Thesis in Leiden Repository
Large parts of the research described in this Thesis aims at the development of oligopeptide-masked toxins and their in situ immunoproteasome-mediated activation. Chapter 2 focuses on the development of selective fluorogenic substrates for each of the iCP and cCP proteasome subunits. Chapter 3 describes the utilization of proteasome cleavable linkers in order to release a toxic entity in immunoproteasome expressing cells. By selecting oligopeptide sequences of previously described immunoproteasome-selective fluorogenic substrates and inhibitors, and linking these to doxorubicin via a cleavable linker, new constructs were obtained. Chapter 4 describes an immunoproteasome inhibitor-doxorubicin conjugate that targets multiple myeloma derived cells and releases doxorubicin upon low-dose photon irradiation. Chapter 5 describes how a trans-cyclooctene (TCO) is utilized for the release of a toxic payload via a click to release reaction in conjunction with selective proteasome targeting. TCOs were used in order to facilitate toxin activation via an inverse electron demanding Diels-Alder reaction with tetrazine as a dienophile. Chapter 6 gives insight in the development of pan-immuno subunit selective proteasome inhibitors based on P3 and P4 scaffold exchanges. Finally, the research described in this thesis is summarized in Chapter 7, and future prospects based the presented results are discussed.