Dataset Information

Improvement of Asparagine Ethylenediamines as Anti-malarial Plasmodium-Selective Proteasome Inhibitors.

ABSTRACT: The Plasmodium proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors. Here, we report further a structure-activity relationship study of AsnEDAs for selective inhibition of Pf20S over human proteasomes. Additionally, we show new mutation that conferred resistance to AsnEDAs and collateral sensitivity to an inhibitor of the Pf20S ?2 subunit, the same as previously identified resistant mutation. This resistance could be overcome through the use of the structure-guided inhibitor design. Collateral sensitivity to inhibitors among respective proteasome subunits underscores the potential value of treating malaria with combinations of inhibitors of different proteasome subunits to minimize the emergence of drug resistance.

SUBMITTER: Zhan W

PROVIDER: S-EPMC7104388 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Improvement of Asparagine Ethylenediamines as Anti-malarial <i>Plasmodium</i>-Selective Proteasome Inhibitors.

Zhan Wenhu W Visone Joseph J Ouellette Tierra T Harris Jacob C JC Wang Rong R Zhang Hao H Singh Pradeep K PK Ginn John J Sukenick George G Wong Tzu-Tshin TT Okoro Judith I JI Scales Ryan M RM Tumwebaze Patrick K PK Rosenthal Philip J PJ Kafsack Björn F C BFC Cooper Roland A RA Meinke Peter T PT Kirkman Laura A LA Lin Gang G

Journal of medicinal chemistry 20190620 13

The <i>Plasmodium</i> proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors. Here, we report f ...[more]

PMID: 31177777

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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

Improvement of Asparagine Ethylenediamines as Anti-malarial Plasmodium-Selective Proteasome Inhibitors.

Publications

Improvement of Asparagine Ethylenediamines as Anti-malarial <i>Plasmodium</i>-Selective Proteasome Inhibitors.

Similar Datasets

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