Hamilton David J, Ábrányi-Balogh Péter, Keeley Aaron, Petri László, Hrast Martina, Imre Tímea, Wijtmans Maikel, Gobec Stanislav, Esch Iwan J P de, Keserű György Miklós
Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok krt 2, H-1117 Budapest, Hungary.
Pharmaceuticals (Basel). 2020 Nov 3;13(11):362. doi: 10.3390/ph13110362.
Drug discovery programs against the antibacterial target UDP--acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads. The electrophilic reactivity and cysteine specificity have been determined in a glutathione (GSH) and an oligopeptide assay, respectively. Investigating the structure-activity relationship for MurA suggests a crucial role for the bromine atom in the ligand. In addition, MS/MS experiments have proven the covalent labelling of MurA at Cys115 and the observed loss of the bromine atom suggests a net nucleophilic substitution as the covalent reaction. This new set of compounds might be considered as a viable chemical starting point for the discovery of new MurA inhibitors.
针对抗菌靶点尿苷二磷酸-N-乙酰葡糖胺烯醇丙酮酸转移酶（MurA）的药物研发项目已经产生了具有小三元和五元杂环的共价抑制剂。在当前的研究中，对四元环的反应活性进行了精细调控，以获得一类新型的共价MurA抑制剂。对一个小的环丁烯酮衍生物文库进行筛选，鉴定出溴代环丁烯胺酮作为新的亲电弹头。分别在谷胱甘肽（GSH）和寡肽试验中测定了亲电反应活性和对半胱氨酸的特异性。对MurA的构效关系研究表明，配体中的溴原子起着关键作用。此外，串联质谱（MS/MS）实验证明了MurA在半胱氨酸115处的共价标记，观察到的溴原子损失表明共价反应是一个净亲核取代过程。这组新化合物可能被视为发现新型MurA抑制剂的一个可行的化学起始点。
