Open AccessSelective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome
Author(s) -
Zhan Wen-hu,
Hao-Chi Hsu,
Trevor Morgan,
Tierra Ouellette,
Kristin Burns-Huang,
Ryujiro Hara,
A. G. Wright,
Toshihiro Imaeda,
Rei Okamoto,
Kenjiro Sato,
Mayako Michino,
Manoj K. Ramjee,
Kazuyoshi Aso,
Peter T. Meinke,
Michael A. Foley,
Carl Nathan,
Huilin Li,
Gang Lin
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01187
Subject(s) - proteasome , chemistry , mycobacterium tuberculosis , peptidomimetic , in vitro , microbiology and biotechnology , tuberculosis , biochemistry , biology , peptide , medicine , pathology
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.