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Microbiology and Immunology

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Selective Phenylimidazole-Based Inhibitors of the Proteasome.

TitleSelective Phenylimidazole-Based Inhibitors of the Proteasome.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhan W, Hsu H-C, Morgan T, Ouellette T, Burns-Huang K, Hara R, Wright AG, Imaeda T, Okamoto R, Sato K, Michino M, Ramjee M, Aso K, Meinke PT, Foley M, Nathan C, Li H, Lin G
JournalJ Med Chem
Date Published2019 Oct 24

Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, (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.

Alternate JournalJ. Med. Chem.
PubMed ID31560200

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