Inhibitors of phosphopantetheine adenylyltransferase.
Eur J Med Chem
; 38(4): 345-9, 2003 Apr.
Article
in En
| MEDLINE
| ID: mdl-12750020
ABSTRACT
Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and tested against Escherichia coli PPAT. The most potent inhibitor PTX040334 was co-crystallised with E. coli PPAT. With this structural information, a rational iterative medicinal chemistry program was initiated, aimed at increasing the number of inhibitor-enzyme interactions. A very potent and specific inhibitor, PTX042695, with an IC(50) of 6 nM against E.coli PPAT, but with no activity against porcine PPAT, was obtained.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dipeptides
/
Enzyme Inhibitors
/
Nucleotidyltransferases
Language:
En
Journal:
Eur J Med Chem
Year:
2003
Document type:
Article
Affiliation country:
United kingdom