Selective inhibitors of the plasmodium proteasome as novel anti-malaria agents
Abstract/Contents
- Abstract
- Malaria, a disease that affects millions of people in the world, is caused by the parasitic protozoan Plasmodium spp. In particular, Plasmodium falciparum leads to the most severe form of malaria and is especially lethal to young children. Although current anti-malaria medications are effective chemotherapeutics, the parasite can rapidly develop resistance to these agents and cases of resistance to even the first line of anti-malaria treatments have been reported. This increases the urgency to identify new malaria drugs and drug targets. In this thesis, I will first describe our efforts at identifying epoxyketone proteasome inhibitors that can attenuate Plasmodium growth with overall low host toxicity. We then synthesized activity based probes to monitor Plasmodium proteasome activity and together with subunit selective proteasome inhibitors, we assessed the importance of individual catalytic sites of the proteasome for parasite survival. We then screened covalent and non-covalent inhibitors against the catalytic site most crucial for parasite viability. Finally, we profiled the substrate cleavage signature of the P. falciparum proteasome and compared it to the human proteasome. We designed peptidic inhibitors based on dominant amino acid residues in the cleavages unique to P. falciparum proteasome. The inhibitor studies, along with cryo-electronmicroscopy structural elucidation of inhibitor bound Plasmodium proteasome, led us to the finding that the host and parasite [beta] 2 proteasome subunit have major differences in their substrate binding site. We then demonstrated how this difference could be exploited for design of potent and parasite selective proteasome inhibitor that was safely dosed in vivo. Taken together, this suggests that the Plasmodium proteasome is sufficiently different from the human proteasome for selective inhibition and promises to be an effective target for anti-malarial therapy.
Description
Type of resource | text |
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Form | electronic; electronic resource; remote |
Extent | 1 online resource. |
Publication date | 2015 |
Issuance | monographic |
Language | English |
Creators/Contributors
Associated with | Li, Hao | |
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Associated with | Stanford University, Department of Chemical and Systems Biology. | |
Primary advisor | Bogyo, Matthew, 1971- | |
Thesis advisor | Bogyo, Matthew, 1971- | |
Thesis advisor | Boothroyd, John, 1948- | |
Thesis advisor | Chen, James | |
Thesis advisor | Mochly-Rosen, Daria | |
Advisor | Boothroyd, John, 1948- | |
Advisor | Chen, James | |
Advisor | Mochly-Rosen, Daria |
Subjects
Genre | Theses |
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Bibliographic information
Statement of responsibility | Hao Li. |
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Note | Submitted to the Department of Chemical and Systems Biology. |
Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Hao Li
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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