Parallel Synthesis and Quantitative Structure-Activity Relationship (QSAR) Modeling of Aminoglycoside-Derived Lipopolymers for Transgene Expression.
Parallel Synthesis and Quantitative Structure-Activity Relationship (QSAR) Modeling of Aminoglycoside-Derived Lipopolymers for Transgene Expression.
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用于转基因表达的氨基糖苷衍生脂质聚合物的平行合成和定量构效关系 (QSAR) 建模。
DOI：
10.1021/acsbiomaterials.5b00045
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发表时间：
2015
影响因子：
5.8
通讯作者：
K. Rege
中科院分区：
文献类型：
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作者：
Bhavani Miryala;Zhuo Zhen;Thrimoorthy Potta;C. Breneman;K. Rege
我们描述了烷酰氯与氨基糖苷类抗生素单体衍生的聚合物的平行合成，作为在哺乳动物细胞中转基因传递和表达的新载体。脂聚合物的平行筛选导致鉴定出六个在几个癌细胞中表现出比亲本聚合物以及25 kDa聚乙二亚胺(目前聚合物介导的转基因表达的标准)更高的转基因表达效率的先导。采用基于定量构效关系(QSAR)的化学信息学模型，研究脂聚合物的物理化学性质(分子描述符)对转基因表达效率的影响。QSAR模型的预测能力，使用未用于模型训练的脂类聚合物进行研究，显示出与实验观察到的转基因表达良好的一致性。我们的发现表明，与未取代的聚合物相比，氨基糖苷类聚合物上的脂质取代导致了高水平的转基因表达。综上所述，这些材料在非病毒转基因传递方面显示出巨大的前景，在生物技术和医学中有几个应用。
We describe the parallel synthesis of lipopolymers generated by conjugating alkanoyl chlorides to polymers derived from aminoglycoside antibiotic monomers as novel vehicles for transgene delivery and expression in mammalian cells. Parallel screening of lipopolymers led to the identification of six leads that demonstrated higher transgene expression efficacies in several cancer cells, when compared to the parental polymers as well as 25 kDa poly(ethylene imine), a current standard for polymer-mediated transgene expression. Quantitiative structure-activity relationship (QSAR)-based cheminformatics modeling was employed in order to investigate the role of lipopolymer physicochemical properties (molecular descriptors) on transgene expression efficacy. The predictive ability of the QSAR model, investgated using lipopolymers not employed for training the model, demonstrated excellent agreement with experimentally observed transgene expression. Our findings indicate that lipid substitution on aminoglycoside-derived polymers results in high levels of transgene expression compared to unsubstituted polymers. Taken together, these materials show significant promise in nonviral transgene delivery with several applications in biotechnology and medicine.