Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
Int J Mol Sci. 2021 Jan 28;22(3):1274. doi: 10.3390/ijms22031274.
MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nucleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting material. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.
MTH1 是一种酶，能够将核苷酸池中的 8-氧代-dGTP（一种氧化损伤的碱基）水解为 8-氧代-dGMP，以防止其错误掺入基因组 DNA 中。具有选择性和高亲和力的 MTH1 结合分子具有作为生物工具和药物候选物的潜力。我们最近开发了 8-卤代 7-脱氮-dGTP 作为 8-氧代-dGTP 的类似物，发现它不能被水解，但能抑制酶活性。为了进一步增加 MTH1 结合，我们设计并合成了 7,8-二卤代 7-脱氮-dG 衍生物。我们成功地使用 7-脱氮-dG 作为起始原料合成了多种衍生物，包括取代核苷和核苷酸。对 MTH1 活性的抑制评估显示，7,8-二卤代 7-脱氮-dG 衍生物对酶活性具有很强的抑制作用，特别是 7,8-二溴 7-脱氮-dGTP。基于动力学参数的结果和模拟研究的计算对接，这些核苷酸类似物与 MTH1 的活性位点相互作用，并竞争性抑制底物 8-氧代-dGTP。因此，新化合物的使用可能阐明细胞中修复酶的新特性。
