Berney Mark, Manoj Manav T, Fay Ellen M, McGouran Joanna F
School of Chemistry & Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, D20 PN40, Ireland.
ChemMedChem. 2022 Mar 4;17(5):e202100603. doi: 10.1002/cmdc.202100603. Epub 2022 Jan 11.
Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co-ordinating 5'-3' exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc-binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate-binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5'-position, as well as zinc-binding groups at the 3'-position, were prepared and tested in gel-electrophoresis and real-time fluorescence assays. As well as investigating novel zinc-binding groups, we found that incorporation of a 5'-phosphate dramatically increased the potency of the inhibitors.
某些癌症表现出DNA链间交联修复途径的上调，这导致对交联化疗药物产生抗性并预后不良。因此，抑制与链间交联修复相关的酶是提高癌症治疗疗效的一种有前景的策略。一种这样的靶酶是SNM1A，一种锌配位的5'-3'核酸外切酶。先前的研究已经证明了使用 appended with zinc-binding groups修饰核苷抑制SNM1A的可行性。在这项工作中，我们试图通过利用与酶活性位点相邻的磷酸结合口袋的相互作用以及催化锌离子来开发更有效的SNM1A抑制剂。制备了一系列在5'-位带有磷酸基团以及在3'-位带有锌结合基团的核苷衍生物，并在凝胶电泳和实时荧光测定中进行了测试。除了研究新型锌结合基团外，我们还发现引入5'-磷酸显著提高了抑制剂的效力。
