| Autor: |
Hao, Zhang, Hao-Chi, Hsu, Shoshanna C, Kahne, Ryoma, Hara, Wenhu, Zhan, Xiuju, Jiang, Kristin, Burns-Huang, Tierra, Ouellette, Toshihiro, Imaeda, Rei, Okamoto, Masanori, Kawasaki, Mayako, Michino, Tzu-Tshin, Wong, Akinori, Toita, Takafumi, Yukawa, Francesca, Moraca, Jeremie, Vendome, Priya, Saha, Kenjiro, Sato, Kazuyoshi, Aso, John, Ginn, Peter T, Meinke, Michael, Foley, Carl F, Nathan, K Heran, Darwin, Huilin, Li, Gang, Lin |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
J Med Chem |
| ISSN: |
1520-4804 |
| Popis: |
Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) are phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill non-replicating (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 co-crystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose-dependently led to accumulation of Pup-tagged GFP that is degradable but resistant to depupylation., and death of non-replicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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