6WNK

Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome

Summary for 6WNK

• Entry DOI: 10.2210/pdb6wnk/pdb
• Related PRD ID: PRD_002377
• Descriptor: 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)
• Functional Keywords: mycobacterium tuberculosis, proteasome inhibitor, macrocyclic peptides, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 28
• Total formula weight: 730000.32

Authors

Hsu, H.C.,Li, H. (deposition date: 2020-04-22, release date: 2021-04-28, Last modification date: 2023-10-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.28 Å)