Xiao Yi, Yi Haomin, Zhu Jingzhi, Chen Suhua, Wang Guofang, Liao Yilong, Lei Yuanyuan, Chen Liyin, Zhang Xingcai, Ye Fangfu
School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.
Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China.
Bioact Mater. 2022 Nov 9;23:45-52. doi: 10.1016/j.bioactmat.2022.10.002. eCollection 2023 May.
Toxicity assessment is a major problem in pharmaceutical candidates and industry chemicals development. However, due to the lack of practical analytical methods for DNA adduct analysis, the safety evaluation of drug and industry chemicals was severely limited. Here, we develop a DNAzyme-based method to detect DNA adduct damage for toxicity assessment of drugs and chemicals. Among 18 structural variants of G4 DNAzyme, EA2 DNAzyme exhibits an obvious DNA damaging effect of styrene oxide (SO) due to its unstable structure. The covalent binding of SO to DNAzyme disrupts the Hoogsteen hydrogen bonding sites of G-plane guanines and affects the formation of the G4 quadruplex. DNA damage chemicals reduce the peroxidase activity of the G4 DNAzyme to monitor the DNA adduct damage by disrupting the structural integrity of the G4 DNAzyme. Our method for genotoxic assessment of pharmaceutical candidates and industrial chemicals can elucidate the complex chemical pathways leading to toxicity, predict toxic effects of chemicals, and evaluate possible risks to human health.
毒性评估是药物候选物和工业化学品开发中的一个主要问题。然而，由于缺乏用于DNA加合物分析的实用分析方法，药物和工业化学品的安全性评估受到严重限制。在此，我们开发了一种基于DNAzyme的方法来检测DNA加合物损伤，用于药物和化学品的毒性评估。在G4 DNAzyme的18种结构变体中，EA2 DNAzyme由于其不稳定的结构而对环氧苯乙烯（SO）表现出明显的DNA损伤作用。SO与DNAzyme的共价结合破坏了G平面鸟嘌呤的Hoogsteen氢键位点，并影响了G4四链体的形成。DNA损伤化学品通过破坏G4 DNAzyme的结构完整性来降低G4 DNAzyme的过氧化物酶活性，以监测DNA加合物损伤。我们用于药物候选物和工业化学品遗传毒性评估的方法可以阐明导致毒性的复杂化学途径，预测化学品的毒性作用，并评估对人类健康的潜在风险。
