德国莱布尼兹材料研究所Andreas Herrmann团队提出了利用机械化学键断裂进行药物活化的策略。 相关研究成果发表在2021年1月29日出版的《自然—化学》。

药物治疗常常因药物选择性差而受到阻碍，包括不必要的副作用和耐药性。空间和时间上控制药物活化对刺激的反应是一个有希望减轻和规避这些问题的策略。

该文中，研究人员使用超声波通过机械化学力使不稳定的共价键和弱的非共价键受控断裂，最终实现从非活性大分子或纳米组装体中激活药物。研究人员发现在主链中心具有二硫键基序的聚合物通过力诱导的分子内5-exo-trig环化从其β-碳酸盐连接体释放基于生物碱的抗癌药物。其次，氨基糖苷类抗生素与多适体RNA结构复合后，通过核酸骨架的机械化学力开放和断裂被激活。最后，通过肽类抗生素万古霉素与其互补肽靶点之间的氢键连接在一起的纳米粒子-聚合物和纳米粒子-纳米粒子组装体被力诱导氢键断裂而激活。

该i项工作证明了超声波激活机械响应前药系统的潜力。

附：英文原文

Title: Mechanochemical bond scission for the activation of drugs

Author: Shuaidong Huo, Pengkun Zhao, Zhiyuan Shi, Miancheng Zou, Xintong Yang, Eliza Warszawik, Mark Loznik, Robert Gstl, Andreas Herrmann

Issue&Volume: 2021-01-29

Abstract: Pharmaceutical drug therapy is often hindered by issues caused by poor drug selectivity, including unwanted side effects and drug resistance. Spatial and temporal control over drug activation in response to stimuli is a promising strategy to attenuate and circumvent these problems. Here we use ultrasound to activate drugs from inactive macromolecules or nano-assemblies through the controlled scission of mechanochemically labile covalent bonds and weak non-covalent bonds. We show that a polymer with a disulfide motif at the centre of the main chain releases an alkaloid-based anticancer drug from its β-carbonate linker by a force-induced intramolecular 5-exo-trig cyclization. Second, aminoglycoside antibiotics complexed by a multi-aptamer RNA structure are activated by the mechanochemical opening and scission of the nucleic acid backbone. Lastly, nanoparticle–polymer and nanoparticle–nanoparticle assemblies held together by hydrogen bonds between the peptide antibiotic vancomycin and its complementary peptide target are activated by force-induced scission of hydrogen bonds. This work demonstrates the potential of ultrasound to activate mechanoresponsive prodrug systems.

DOI: 10.1038/s41557-020-00624-8

Source: https://www.nature.com/articles/s41557-020-00624-8