Dataset Information

Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome.

ABSTRACT: Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.

SUBMITTER: Zhan W

PROVIDER: S-EPMC7091493 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Selective Phenylimidazole-Based Inhibitors of the <i>Mycobacterium tuberculosis</i> Proteasome.

Zhan Wenhu W Hsu Hao-Chi HC Morgan Trevor T Ouellette Tierra T Burns-Huang Kristin K Hara Ryoma R Wright Adrian G AG Imaeda Toshihiro T Okamoto Rei R Sato Kenjiro K Michino Mayako M Ramjee Manoj M Aso Kazuyoshi K Meinke Peter T PT Foley Michael M Nathan Carl F CF Li Huilin H Lin Gang G

Journal of medicinal chemistry 20191015 20

Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, <i>Mycobacterium tuberculosis</i> (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for an ...[more]

PMID: 31560200

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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 ?2-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 ?2 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 ?2-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

Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome.

Publications

Selective Phenylimidazole-Based Inhibitors of the <i>Mycobacterium tuberculosis</i> Proteasome.

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