1446253-08-2Relevant academic research and scientific papers
Assay platform for clinically relevant metallo-β-lactamases
Van Berkel, Sander S.,Brem, Jürgen,Rydzik, Anna M.,Salimraj, Ramya,Cain, Ricky,Verma, Anil,Owens, Raymond J.,Fishwick, Colin W.G.,Spencer, James,Schofield, Christopher J.
, p. 6945 - 6953 (2013/10/01)
Metallo-β-lactamases (MBLs) are a growing threat to the use of almost all clinically used β-lactam antibiotics. The identification of broad-spectrum MBL inhibitors is hampered by the lack of a suitable screening platform, consisting of appropriate substrates and a set of clinically relevant MBLs. We report procedures for the preparation of a set of clinically relevant metallo-β-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (Sa?o Paulo MBL), and VIM-2 (Verona integron-encoded MBL)) and the identification of suitable fluorogenic substrates (umbelliferone-derived cephalosporins). The fluorogenic substrates were compared to chromogenic substrates (CENTA, nitrocefin, and imipenem), showing improved sensitivity and kinetic parameters. The efficiency of the fluorogenic substrates was exemplified by inhibitor screening, identifying 4-chloroisoquinolinols as potential pan MBL inhibitors.
Structural basis for inhibition of the fat mass and obesity associated protein (FTO)
Aik, Weishen,Demetriades, Marina,Hamdan, Muhammad K. K.,Bagg, Eleanor. A. L.,Yeoh, Kar Kheng,Lejeune, Clarisse,Zhang, Zhihong,McDonough, Michael A.,Schofield, Christopher J.
, p. 3680 - 3688 (2013/06/27)
The fat mass and obesity associated protein (FTO) is a potential target for anti-obesity medicines. FTO is a 2-oxoglutarate (2OG)-dependent N-methyl nucleic acid demethylase that acts on substrates including 3-methylthymidine, 3-methyluracil, and 6-methyladenine. To identify FTO inhibitors, we screened a set of 2OG analogues and related compounds using differential scanning fluorometry-and liquid chromatography-based assays. The results revealed sets of both cyclic and acyclic 2OG analogues that are FTO inhibitors. Identified inhibitors include small molecules that have been used in clinical studies for the inhibition of other 2OG oxygenases. Crystallographic analyses reveal inhibition by 2OG cosubstrate or primary substrate competitors as well as compounds that bind across both cosubstrate and primary substrate binding sites. The results will aid the development of more potent and selective FTO inhibitors.
