Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.
ACS Infect Dis
; 10(5): 1561-1575, 2024 05 10.
Article
en En
| MEDLINE
| ID: mdl-38577994
ABSTRACT
DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Tioléster Hidrolasas
/
Sintasas Poliquetidas
/
Inhibidores Enzimáticos
/
Bibliotecas de Moléculas Pequeñas
/
Mycobacterium tuberculosis
/
Antituberculosos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
ACS Infect Dis
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos