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 IC50 of 6 nM against E.coli PPAT, but with no activity against porcine PPAT, was obtained. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.