摘要
嘌呤反向Hoogsteen(PPRH)分子是由两条以反向平行取向运行并且不含核苷酸修饰的多个嘌呤链形成的DNA发夹。通过五标肽环连接的两条链通过分子内反向Hoogsteen键结合。然后,PPRH可以通过Watson-Crick键与其对应的双链DNA中的多嘧啶靶标结合,从而引起双链体的聚脲链的置换。我们使用针对dhfr基因的模板和编码链设计的PPRH来描述PPRH在细胞中的作用和作用机制。在异种移植前列腺癌肿瘤模型中,使用针对存活蛋白的PPRH建立PPRH作为治疗工具的原理证明。为了提高PPRHs效应,研究了长度的影响,通过较长的分子获得更高的效率。为了降低可能的目标效应,当在嘧啶靶中发现嘌呤中断时,PPRH序列应该包含与中断相反的互补碱基的两条链。此外,PPRHs的稳定性高于siRNAs,由前者在不同类型血清和PC3细胞中的较长半衰期证明。 PPRH不诱导转录因子的水平以及参与Toll样受体途径的促炎细胞因子,并且它们不会引发炎性体复合物的形成。 PPRH可用作靶向癌症进展,抗药性或免疫治疗方法的基因的治疗工具。
关键词: PPRHs,癌症,基因沉默,Hoogsteen结合,细胞凋亡,稳定性,免疫治疗。
Current Medicinal Chemistry
Title:Polypurine Reverse Hoogsteen Hairpins as a Gene Silencing Tool for Cancer
Volume: 24 Issue: 26
关键词: PPRHs,癌症,基因沉默,Hoogsteen结合,细胞凋亡,稳定性,免疫治疗。
摘要: Polypurine reverse Hoogsteen (PPRH) molecules are DNA hairpins formed by two polypurine strands running in an antiparallel orientation and containing no nucleotide modifications. The two strands, linked by a pentathymidine loop, are bound through intramolecular reverse Hoogsteen bonds. Then, PPRHs can bind by Watson-Crick bonds to their corresponding polypyrimidine target in the dsDNA provoking a displacement of the polypurine strand of the duplex. We described the effect and mechanisms of action of PPRHs in cells using PPRHs designed against the template and coding strands of the dhfr gene. The proof of principle of PPRHs as a therapeutic tool was established using a PPRH against survivin in a xenograft prostate cancer tumor model. To improve the PPRHs effect, the influence of the length was studied obtaining a higher efficiency with longer molecules. To decrease the possible offtarget effect, when a purine interruption is found in the pyrimidine target, the PPRH sequence should contain both strands of the complementary base opposite to the interruption. Furthermore, the stability of PPRHs is higher than that of siRNAs, as evidenced by the longer halflife of the former in different types of serum and in PC3 cells. PPRHs do not induce the levels of the transcription factors nor the proinflammatory cytokines involved in the Toll-like Receptor pathway and they do not trigger the formation of the inflammasome complex. PPRHs can be used as therapeutic tools to target genes related to cancer progression, resistance to drugs or immunotherapy approaches.
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Polypurine Reverse Hoogsteen Hairpins as a Gene Silencing Tool for Cancer, Current Medicinal Chemistry 2017; 24 (26) . https://dx.doi.org/10.2174/0929867324666170301114127
DOI https://dx.doi.org/10.2174/0929867324666170301114127 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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