Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome.

TitleRational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome.
Publication TypeJournal Article
Year of Publication2017
AuthorsTotaro KA, Barthelme D, Simpson PT, Jiang X, Lin G, Nathan C, Sauer RT, Sello JK
JournalACS Infect Dis
Volume3
Issue2
Pagination176-181
Date Published2017 02 10
ISSN2373-8227
KeywordsCell Line, Drug Design, Humans, Models, Molecular, Mycobacterium tuberculosis, Peptides, Cyclic, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Binding, Substrate Specificity
Abstract

The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans. Selective inhibitors of the Mtb 20S were designed and synthesized on the bases of both its unique substrate preferences and the structures of substrate-mimicking covalent inhibitors of eukaryotic proteasomes called syringolins. Unlike the parent syringolins, the designed analogues weakly inhibit the human 20S (Hs 20S) proteasome and preferentially inhibit Mtb 20S over the human counterpart by as much as 74-fold. Moreover, they can penetrate the mycobacterial cell envelope and render Mtb susceptible to nitric oxide-mediated stress. Importantly, they do not inhibit the growth of human cell lines in vitro and thus may be starting points for tuberculosis drug development.

DOI10.1021/acsinfecdis.6b00172
Alternate JournalACS Infect Dis
PubMed ID28183185
PubMed Central IDPMC5410965
Grant ListR01 AI016892 / AI / NIAID NIH HHS / United States
R21 AI101393 / AI / NIAID NIH HHS / United States
R21 AI123794 / AI / NIAID NIH HHS / United States
U19 AI111143 / AI / NIAID NIH HHS / United States

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