Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.
J Med Chem
; 64(9): 6262-6272, 2021 05 13.
Article
em 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos Cíclicos
/
Complexo de Endopeptidases do Proteassoma
/
Inibidores de Proteassoma
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Mycobacterium tuberculosis
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos