6WNK

Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome

6WNK の概要

• エントリーDOI: 10.2210/pdb6wnk/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002377
• 分子名称: Proteasome subunit alpha, Proteasome subunit beta, (12S,15S)-N-[(2-fluorophenyl)methyl]-10,13-dioxo-12-{2-oxo-2-[(2R)-2-phenylpyrrolidin-1-yl]ethyl}-2-oxa-11,14-diazatricyclo[15.2.2.1~3,7~]docosa-1(19),3(22),4,6,17,20-hexaene-15-carboxamide, ... (6 entities in total)
• 機能のキーワード: mycobacterium tuberculosis, proteasome inhibitor, macrocyclic peptides, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 730000.32

構造登録者

Hsu, H.C.,Li, H. (登録日: 2020-04-22, 公開日: 2021-04-28, 最終更新日: 2023-10-18)

主引用文献

Zhang, H.,Hsu, H.C.,Kahne, S.C.,Hara, R.,Zhan, W.,Jiang, X.,Burns-Huang, K.,Ouellette, T.,Imaeda, T.,Okamoto, R.,Kawasaki, M.,Michino, M.,Wong, T.T.,Toita, A.,Yukawa, T.,Moraca, F.,Vendome, J.,Saha, P.,Sato, K.,Aso, K.,Ginn, J.,Meinke, P.T.,Foley, M.,Nathan, C.F.,Darwin, K.H.,Li, H.,Lin, G.
Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.
J.Med.Chem., 64:6262-6272, 2021

PubMed Abstract: Treatment of tuberculosis (TB) currently takes at least 6 months. Latent (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 . The cocrystal structure of macrocycle with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 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.

PubMed: 33949190
DOI: 10.1021/acs.jmedchem.1c00296

実験手法

X-RAY DIFFRACTION (2.28 Å)