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Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.
Zhang, Hao; Hsu, Hao-Chi; Kahne, Shoshanna C; Hara, Ryoma; Zhan, Wenhu; Jiang, Xiuju; Burns-Huang, Kristin; Ouellette, Tierra; Imaeda, Toshihiro; Okamoto, Rei; Kawasaki, Masanori; Michino, Mayako; Wong, Tzu-Tshin; Toita, Akinori; Yukawa, Takafumi; Moraca, Francesca; Vendome, Jeremie; Saha, Priya; Sato, Kenjiro; Aso, Kazuyoshi; Ginn, John; Meinke, Peter T; Foley, Michael; Nathan, Carl F; Darwin, K Heran; Li, Huilin; Lin, Gang.
  • Zhang H; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Hsu HC; Department of Structural Biology, Van Andel Institute, 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
  • Kahne SC; Department of Microbiology, New York University School of Medicine, 430 E. 29th Street, New York, New York 10016, United States.
  • Hara R; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Zhan W; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Jiang X; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Burns-Huang K; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Ouellette T; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Imaeda T; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Okamoto R; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Kawasaki M; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Michino M; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Wong TT; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Toita A; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Yukawa T; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Moraca F; Schrödinger, Inc., New York, New York 10036, United States.
  • Vendome J; Schrödinger, Inc., New York, New York 10036, United States.
  • Saha P; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Sato K; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Aso K; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Ginn J; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Meinke PT; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Foley M; Tri-Institutional Therapeutics Discovery Institute, 413 E. 69th Street, New York, New York 10065, United States.
  • Nathan CF; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
  • Darwin KH; Department of Microbiology, New York University School of Medicine, 430 E. 29th Street, New York, New York 10016, United States.
  • Li H; Department of Structural Biology, Van Andel Institute, 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
  • Lin G; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.
J Med Chem ; 64(9): 6262-6272, 2021 05 13.
Article en En | MEDLINE | ID: mdl-33949190
ABSTRACT
Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Péptidos Cíclicos / Complejo de la Endopetidasa Proteasomal / Inhibidores de Proteasoma / Mycobacterium tuberculosis Límite: Humans Idioma: En Año: 2021 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Péptidos Cíclicos / Complejo de la Endopetidasa Proteasomal / Inhibidores de Proteasoma / Mycobacterium tuberculosis Límite: Humans Idioma: En Año: 2021 Tipo del documento: Article