Bogdan Florea

The ubiquitin-proteasome system (UPS) is a potential pathway for therapeutic intervention for pathogens such as Plasmodium, the causative agent of malaria. However, due to the essential nature of this proteolytic pathway, proteasome inhibitors must avoid inhibition of the host enzyme complex to prevent toxic side effects. The Plasmodium proteasome is poorly characterized, making rational design of inhibitors that induce selective parasite killing difficult. In this study, we developed a chemical probe that labels all catalytic sites of the Plasmodium proteasome. Using this probe, we identified several subunit selective small molecule inhibitors of the parasite enzyme complex. Treatment with an inhibitor that is specific for the β5 subunit during blood stage schizogony led to a dramatic decrease in parasite replication while short-term inhibition of the β2 subunit did not affect viability. Interestingly, coinhibition of both the β2 and β5 catalytic subunits resulted in enhanced parasite killing at all stages of the blood stage life cycle and reduced parasite levels in vivo to barely detectable levels. Parasite killing was achieved with overall low host toxicity, something that has not been possible with existing proteasome inhibitors. Our results highlight differences in the subunit dependency of the parasite and human proteasome, thus providing a strategy for development of potent antimalarial drugs with overall low host toxicity.

Chapter 13 Bronchial epithelial cell cultures Claire Meaney, Bogdan I. Florea, Carsten Ehrhardt, Ulrich F. Schäfer, Claus-Michael Lehr, Hans E. Junginger and Gerrit Borchard INTRODUCTION Physiology of the bronchial epithelium The conducting airways consist of the trachea, ...

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The synthesis and evaluation of hybrid proteasome inhibitors that contain structural elements of the known inhibitors bortezomib, epoxomicin and peptide vinyl sulfones is described. From the panel of 15 inhibitors some structure activity relationships can be deduced with regard to inhibitory activity in relation to peptide recognition element, inhibitor size and nature of the electrophilic trap. Further, the panel contains one of the most potent peptide-based pan-proteasome inhibitors reported to date.

A new class of potent proteasome inhibitors is described, of which the members contain an amino acid inspired sulfonyl fluoride as the electrophilic trap. In total, 24 peptido sulfonyl fluoride inhibitors have been designed and synthesized, which were inspired by the backbone sequences of the proteasome inhibitors bortezomib, epoxomicin, and Cbz-Leu(3)-aldehyde. Nine of them were very potent proteasome inhibitors, the best of which had an IC(50) of 7 nM. A number of the peptido sulfonyl fluoride inhibitors were found to be highly selective for the β5 proteasome subunit.

... Microreview. Chemical Tools To Study the Proteasome. Martijn Verdoes,; Bogdan I. Florea,; Gijsbert A. van der Marel,; Herman S. Overkleeft. Article first published online: 16 APR 2009. DOI: 10.1002/ejoc.200900075. Copyright © 2009 WILEY-VCH Verlag GmbH & Co. ...