1. Cephalosporins inhibit human metallo β-lactamase fold DNA repair nucleases SNM1A and SNM1B/apollo.
- Author
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Lee SY, Brem J, Pettinati I, Claridge TD, Gileadi O, Schofield CJ, and McHugh PJ
- Subjects
- Cell Cycle Proteins, Cephalosporins chemical synthesis, Cephalosporins chemistry, DNA Repair Enzymes metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Exodeoxyribonucleases metabolism, Humans, Models, Molecular, Molecular Conformation, Nuclear Proteins metabolism, Structure-Activity Relationship, Cephalosporins pharmacology, DNA Repair drug effects, DNA Repair Enzymes antagonists & inhibitors, Enzyme Inhibitors pharmacology, Exodeoxyribonucleases antagonists & inhibitors, Nuclear Proteins antagonists & inhibitors, beta-Lactamases metabolism
- Abstract
Bacterial metallo-β-lactamases (MBLs) are involved in resistance to β-lactam antibiotics including cephalosporins. Human SNM1A and SNM1B are MBL superfamily exonucleases that play a key role in the repair of DNA interstrand cross-links, which are induced by antitumour chemotherapeutics, and are therefore targets for cancer chemosensitization. We report that cephalosporins are competitive inhibitors of SNM1A and SNM1B exonuclease activity; both the intact β-lactam and their hydrolysed products are active. This discovery provides a lead for the development of potent and selective SNM1A and SNM1B inhibitors.
- Published
- 2016
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