Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome.
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.
Department of Chemistry, Brown University , 324 Brook Street, Box H, Providence, Rhode Island 02912, United States.
Kyle A
0000-0001-6824-7999
KA
Totaro
Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, 68-571A, Cambridge, Massachusetts 02139, United States.
Dominik
D
Barthelme
Department of Chemistry, Brown University , 324 Brook Street, Box H, Providence, Rhode Island 02912, United States.
Peter T
PT
Simpson
Department of Microbiology and Immunology, Weill Cornell Medicine , 1300 York Avenue, New York, New York 10065, United States.
Xiuju
X
Jiang
Department of Microbiology and Immunology, Weill Cornell Medicine , 1300 York Avenue, New York, New York 10065, United States.
Gang
G
Lin
Department of Microbiology and Immunology, Weill Cornell Medicine , 1300 York Avenue, New York, New York 10065, United States.
Carl F
CF
Nathan
Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, 68-571A, Cambridge, Massachusetts 02139, United States.
Robert T
RT
Sauer
Department of Chemistry, Brown University , 324 Brook Street, Box H, Providence, Rhode Island 02912, United States.
Jason K
0000-0001-6263-7902
JK
Sello
D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013379:Substrate Specificity
D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
host−pathogen interaction; innate immune response; nitric oxide; peptidomimetic; protein homeostasis; syringolins