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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Zhan W,Hsu HC,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 CF,Li H,Lin Gdoi
10.1021/acs.jmedchem.9b01187subject
Has Abstractpub_date
2019-10-24 00:00:00pages
9246-9253issue
20eissn
0022-2623issn
1520-4804journal_volume
62pub_type
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