Martin James S, Mackenzie Claire J, Lin De, Homeyer Nadine, Gray David W, Zuccotto Fabio, Gilbert Ian H
Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, United Kingdom.
ACS Omega. 2023 Mar 27;8(14):12787-12804. doi: 10.1021/acsomega.2c08031. eCollection 2023 Apr 11.
There is an urgent need for the development of new therapeutics with novel modes of action to target Gram-negative bacterial infections, due to resistance to current drugs. Previously, FabA, an enzyme in the bacterial type II fatty acid biosynthesis pathway, was identified as a potential drug target in , a Gram-negative bacteria of significant clinical concern. A chemical starting point was also identified. There is a cysteine, Cys15, in the active site of FabA, adjacent to where this compound binds. This paper describes the preparation of analogues containing an electrophilic warhead with the aim of covalent inhibition of the target. A wide variety of analogues were successfully prepared. Unfortunately, these analogues did not increase inhibition, which may be due to a loop within the enzyme partially occluding access to the cysteine.
由于对现有药物产生耐药性，迫切需要开发具有新型作用模式的新疗法来治疗革兰氏阴性菌感染。此前，细菌II型脂肪酸生物合成途径中的一种酶FabA，在一种具有重大临床意义的革兰氏阴性菌中被确定为潜在的药物靶点。还确定了一个化学起始点。在FabA的活性位点有一个半胱氨酸Cys15，与该化合物结合的位置相邻。本文描述了含有亲电弹头的类似物的制备，目的是对靶点进行共价抑制。成功制备了多种类似物。遗憾的是，这些类似物并没有增强抑制作用，这可能是由于酶中的一个环部分阻碍了对半胱氨酸的接近。
