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Structure-Based Design of Inhibitors Selective for Human Proteasome ?2c or ?2i Subunits.

ABSTRACT: Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the ?1c, ?1i, ?5c, and ?5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting ?2c or ?2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the ?2c- and ?2i-selective compounds LU-002c (4; IC50 ?2c: 8 nM, IC50 ?2i/?2c: 40-fold) and LU-002i (5; IC50 ?2i: 220 nM, IC50 ?2c/?2i: 45-fold), respectively. Co-crystal structures with ?2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of ?2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.

SUBMITTER: Xin BT

PROVIDER: S-EPMC6378654 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits.

Xin Bo-Tao BT Huber Eva M EM de Bruin Gerjan G Heinemeyer Wolfgang W Maurits Elmer E Espinal Christofer C Du Yimeng Y Janssens Marissa M Weyburne Emily S ES Kisselev Alexei F AF Florea Bogdan I BI Driessen Christoph C van der Marel Gijsbert A GA Groll Michael M Overkleeft Herman S HS

Journal of medicinal chemistry 20190205 3

Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesi ...[more]

PMID: 30657666

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Project description:The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents.

Dataset Information

Structure-Based Design of Inhibitors Selective for Human Proteasome ?2c or ?2i Subunits.

Publications

Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits.

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