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
in 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Thiolester Hydrolases
/
Polyketide Synthases
/
Enzyme Inhibitors
/
Small Molecule Libraries
/
Mycobacterium tuberculosis
/
Antitubercular Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
ACS Infect Dis
Year:
2024
Type:
Article
Affiliation country:
United States