Inhibitors of phosphopantetheine adenylyltransferase.
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.
Zhao
Lihua
L
Department of Chemistry, PanTherix Ltd, West of Scotland Science Park, Todd Campus, G20 0XA, Glasgow, UK. lihua.zhao@pantherix.co.uk
Allanson
Nigel M
NM
Thomson
Samantha P
SP
Maclean
John K F
JK
Barker
John J
JJ
Primrose
William U
WU
Tyler
Paul D
PD
Lewendon
Ann
A
D003065:Coenzyme A / Q000096:biosynthesis; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004151:Dipeptides; D004791:Enzyme Inhibitors; C481185:PTX040334; C481186:PTX042695; D009713:Nucleotidyltransferases; C022315:pantetheine-phosphate adenylyltransferase; D003065:Coenzyme A