Development of pan-immunoselective proteasome inhibitors
March 2019 – March 2023
Group and collaboration
Collaboration: Prof. Dr. Hermen S. Overkleeft, Dr. Bogdan I. Florea (Leiden University)
PhD student: Patrick Dekker
The proteasome has proven to be a promising drug target in the field of oncology. Several proteasome inhibitors are already actively being used in the clinic for the treatment of haematological cancers, multiple myeloma and mantle cell lymphoma. The proteasome plays a pivotal role in maintaining the delicate balance of protein homeostasis, and in processing epitopes needed for antigen presentation as part of the adaptive immune response. Disrupting protein homeostasis by proteasome inhibition causes the manifestation of cytotoxic protein build-up, leading to cell apoptosis. This has been the main mechanism by which proteasome inhibitors have been used to combat haematological cancers.
Interestingly enough several pathogenic microorganisms, such as Plasmodium falciparum and Mycobacterium tuberculosis, have shown to exhibit a distinctly different proteasomal specificity in comparison with human proteasomal specificity. This enables us to specifically inhibit the microorganism’s proteasome over the human proteasome, thereby using the disruption of the microbial protein homeostasis as a way of treating infections caused by pathogenic microorganisms.
This project will focus on exploring the proteasomal specificity of pathogenic microorganisms and ultimately aims to develop new tools and probes suitable for selectively inhibiting pathogenic microorganisms in the host environment.
- Developing new probes suitable for selectively inhibiting pathogenic microorganisms in the host environment