Zhao Lihua, Allanson Nigel M, Thomson Samantha P, Maclean John K F, Barker John J, Primrose William U, Tyler Paul D, Lewendon Ann
Department of Chemistry, PanTherix Ltd, West of Scotland Science Park, Todd Campus, G20 0XA, Glasgow, UK.
Eur J Med Chem. 2003 Apr;38(4):345-9. doi: 10.1016/s0223-5234(03)00047-3.
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.
磷酸泛酰巯基乙胺腺苷酰转移酶（PPAT）是辅酶A生物合成中的一种关键酶。由于细菌PPAT与哺乳动物PPAT不同，该酶是一个有吸引力的抗菌靶点。基于底物4-磷酸泛酰巯基乙胺的结构，设计、合成了一个二肽文库，并针对大肠杆菌PPAT进行了测试。最有效的抑制剂PTX040334与大肠杆菌PPAT共结晶。利用这一结构信息，启动了一个合理的迭代药物化学程序，旨在增加抑制剂与酶的相互作用数量。获得了一种非常有效且特异性的抑制剂PTX042695，其对大肠杆菌PPAT的IC50为6 nM，但对猪PPAT无活性。
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