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1.
反义核酸技术已被广泛用于治疗药物、药物靶点确认、探知病理基因的表达。目前对其作用原理的研究集中于其被吸收入细胞的机制、在细胞内的分布、反义核酸序列的最佳长度和性质,并针对体内可能抑制反义核酸活性的影响因素,采取了各种相应的反义核酸优化技术,如对反义核酸的化学修饰、联结高效的转运载体、确定最佳的反义结合位点等,通过这些技术来提高其体内稳定性、跨细胞转运的效率,识别靶序列的特异性,以获得更多更好的反义药物投入实用。  相似文献   

2.
反义基因治疗   总被引:4,自引:0,他引:4  
陈云弟 《生物工程进展》2000,20(3):23-26,29
除了反义核酸和核酶外,最近又发展了一种新型的反义药物-反义肽核酸(RNA)。反义治疗的经验策略是阻断异常基因的表达;随着研究的深入,又发现了以反义药物调整基因表达比例(即调控基因治疗)的反义治疗途径。本文对反义基因治疗的策略,反义药物的设计及稳定性等方面的新思路和该领域的发展与应用前景作了概括介绍。  相似文献   

3.
反义技术及其在G蛋白研究中的应用   总被引:2,自引:0,他引:2  
反义技术至少包括反义寡核苷酸技术、反义RNA技术和核酶技术.在G蛋白研究中,反义技术在G蛋白受体及受体亚型研究、G蛋白转导信号特异性研究方面及对G蛋白耦联信号传导途径与其他信号传导途径之间“cross talk”认识方面的研究中,有着广泛的应用.  相似文献   

4.
反义RNA研究新进展   总被引:3,自引:1,他引:2  
近年来,人们不断发现原核生物和真核生物中自然存在的反义RNA,这可能揭示另一个新的基因调控方式。 反义RNA通过碱基配对,特异性地与mRNA结合,阻止mRNA的翻译,从而抑制细胞中内源性或外源性基因的表达。因此,反义RNA技术为基因表达的功能研究以及基因定位和表达量检测提供了一种比常规遗传分析更为有效的方法,也为肿瘤病、病毒病等预防和治疗提供了可能途径。  相似文献   

5.
反义寡核苷酸可以通过与mRNA相互作用调节的基因表达,但是其作用的强弱受多种因素的影响。反义RNA和反义DNA在调节基因的表达方面各有优缺点;采取适当的方法增强反义寡核苷酸的摄取及促进其释放可以大大提高它们的作用效率;反义寡核苷酸在活体内主要经肾脏和肝脏代谢,有一定特异性和非特异性副作用。根据不同的目的,选择适当的反义寡核苷酸用于研究或疾病的治疗与预防,具有很重要的理论意义和现实意义。  相似文献   

6.
除了反义核酸和核酶外,最近又发展了一种新型的反义药物———反义肽核酸(PNA)。反义治疗的经典策略是阻断异常基因的表达;随着研究的深入,又发现了以反义药物调整基因表达比例(即调控基因治疗)的反义治疗途径。本文对反义基因治疗的策略、反义药物的设计及稳定性等方面的新思路和该领域的发展与应用前景作了概括介绍。  相似文献   

7.
目的:研究bFGF反义硫代寡核苷酸增强肿瘤细胞对化疗药物敏感性作用。方法:设计、合成bFGF寡核苷酸,用聚乙烯亚胺(polyemyleneimine,PEI)介导bFGF反义硫代寡核苷酸转染入黑色素瘤B16细胞,MTT法检测bFGF反义硫代寡核苷酸及其与化疗药物联合处理后的细胞增殖率;半定量RT-PCR测定bFGF反义硫代寡核苷酸转染后细胞中bFGF mRNA水平;流式细胞仪分析bFGF反义硫代寡核苷酸诱导的细胞凋亡。结果:bFGF反义硫代寡核苷酸对B16细胞增殖的抑制率为64.8%,且呈剂量依赖效应。B16细胞中bFGF mRNA被bFGF反义硫代寡核苷酸显著降低,为对照细胞的57.9%,且bFGF反义硫代寡核苷酸诱导B16细胞凋亡,凋亡率为41.8%。bFGF反义硫代寡核苷酸转染能显著增强B16细胞对阿霉素、5-氟脲嘧啶及顺铂的敏感性,非特异性硫代寡核苷酸不影响阿霉素、5-氟脲嘧啶及顺铂抑制B16细胞增殖。结论:bFGF反义硫代寡核苷酸显著增强B16细胞的化疗敏感性,表明其可协同化疗药物用于治疗肿瘤。  相似文献   

8.
从下述六方面概括论述了感染性疾病,尤其是病毒病的反义防治研究进展、存在问题、发展对策和应用前景:(一)感染性疾病的公共卫生问题;(二)反义技术的兴起;(三)反义较常规抗病毒疗法的优越性;1、靶点的精确选择;2、出现抗药性病毒变异株的风险可能降低;(1)用特异性不同的多种反义因子联合治疗;(2)定靶高度保守的病毒序列;(3)可用反义定靶调控序列;(四)反义治疗的潜在毒性;(五)反义物能在体内发挥作用吗?(六)可采用什么类型的反义方法?  相似文献   

9.
反义核酸抗肝炎病毒研究进展   总被引:2,自引:0,他引:2  
病毒性肝炎的治疗一直是困扰人类的一个难题.目前可利用的药物仍屈指可数.反义核酸技术的发展为病毒性肝炎的治疗带来了新的希望.利用反义DNA,反义RNA和核酶技术来抑制乙型肝炎病毒,丙型肝炎病毒和丁型肝炎病毒,在体外已进行了大量的研究,体内也进行了一些研究,为临床应用反义核酸治疗病毒性肝炎奠定了基础.  相似文献   

10.
在调节特定基因的表达上,反义RNA是一种重要的手段。但由于存在降解、非特异性转移及安全性等问题,反义RNA在个体基因治疗中无法得到充分利用。受体介导的内吞作用为定向转移反义RNA提供一种运载工具,它可以将反义RNA定向、高效、低毒、高安全性地转移到靶细胞中发挥作用,因而将大大加快反义RNA基因治疗的临床应用。  相似文献   

11.
由MDR1基因过度表达所引起的肿瘤细胞对化疗药物的耐药性,是导致化疗失败的主要原因之一.针对MDR1中一段包含转录启始位点、翻译启始位点和转录正调控区的序列,设计了反义RNA并将其克隆到逆转录病毒载体pLXSN上.用脂质体包裹载体导入MDR1高表达的耐药细胞KBv200中,在反义RNA转染的细胞中,MDR1在mRNA和蛋白水平的表达都有下降,细胞内药物的浓度有所提高,对长春新碱、阿霉素的耐药性分别下降了65%和47%.实验结果表明,反义RNA对MDR1的表达有抑制作用,从而使肿瘤细胞内的药物浓度升高,其耐药程度下降.  相似文献   

12.
CNS Drug Design Based on Principles of Blood-Brain Barrier Transport   总被引:13,自引:0,他引:13  
Abstract: Lipid-soluble small molecules with a molecular mass under a 400–600-Da threshold are transported readily through the blood-brain barrier in vivo owing to lipid-mediated transport. However, other small molecules lacking these particular molecular properties, antisense drugs, and peptide-based pharmaceuticals generally undergo negligible transport through the blood-brain barrier in pharmacologically significant amounts. Therefore, if present day CNS drug discovery programs are to avoid termination caused by negligible blood-brain barrier transport, it is important to merge CNS drug discovery and CNS drug delivery as early as possible in the overall CNS drug development process. Strategies for special formulation that enable drug transport through the blood-brain barrier arise from knowledge of the molecular and cellular biology of blood-brain barrier transport processes.  相似文献   

13.
14.
应用反义RNA技术降低肿瘤细胞的耐药性   总被引:2,自引:0,他引:2  
细胞内的O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)能够修复亚硝脲药物造成的DNA损伤,阻止亚硝脲药物对肿瘤的杀伤作用,使细胞对亚硝脲药物产生耐药性.我们曾经构建了三个表达MGMT反义RNA的逆转录病毒载体,导入对亚硝脲呈抗性的HeLaS3细胞,并...  相似文献   

15.
Summary Due to the increasing interest in the use of oligonucleotide analogues as antisense and antigene drugs, we designed a chiral analogue constituted of a peptidic frame bearing nucleobases in suitable positions (C-PNA). We recently reported the synthesis of four nonnatural α-amino acids with the DNA bases in the lateral chain. In this paper we present an improved synthesis of the Fmoc monomers and their polymerisation to polypeptidic oligonucleotide analogues using a modification of the standard protocol for solid phase peptide synthesis.  相似文献   

16.
Among the multitude of chemical modifications that have been described over the past two decades, oligonucleotide analogs that are modified at the 2'-position of the furanose sugar have been especially useful for improving the drug-like properties of antisense oligonucleotides (ASOs). These modifications bias the sugar pucker towards the 3'-endo-conformation and improve ASO affinity for its biological target (i.e., mRNA). In addition, antisense drugs incorporating 2'-modified nucleotides exhibit enhanced metabolic stability, and improved pharmacokinetic and toxicological properties. Further conformational restriction of the 2'-substituent to the 4'-position of the furanose ring yielded the 2',4'-bridged nucleic acid (BNA) analogs. ASOs containing BNA modifications showed unprecedented increase in binding affinity for target RNA, while also improved nuclease resistance, in vitro and in vivo potency. Several ASO drug candidates containing 2'-modified nucleotides have entered clinical trials and continue to make progress in the clinic for a variety of therapeutic indications.  相似文献   

17.
Antisense activity in living cells has been thought to occur via a mechanism involving both DNA-mediated hybridization arrest of target mRNA and RNase H-mediated mRNA digestion. Therefore an ideal antisense agent should be permeable to the cell and possess capacities (1) to form a thermally stable duplex in vivo with its target, (2) to discriminate between mRNAs with different degrees of complementarity, and (3) to form antisense/RNA complexes that are susceptible to RNase H hydrolysis. A trisamine-modified deoxyuridine derivative of a novel phosphorothioate DNA 15-mer that meets all these criteria is described here. Compared with the unmodified phosphorothioate oligomer, the phosphorothioate derivative exhibits a higher antisense activity as well as reduced cytotoxicity in cells infected with HIV-1. Our data suggest that the melting temperature (T(m)) between antisense DNA and the target mRNA is not only one of the factors contributing to this derivative's improved antisense activity. Also important are an enhanced ability to discriminate between sequences and an increased susceptibility of the DNA/mRNA complex to RNase H hydrolysis. These results will be useful in designing more active, clinically useful antisense drugs.  相似文献   

18.
19.
Validation of antibiotic mode of action in whole bacterial cells is a key step for antibiotic drug discovery. In this study, one potential drug target, enoyl-acyl carrier protein reductase (FabI), an essential enzyme in the fatty acid biosynthesis pathway, was used to evaluate the feasibility of using a regulated antisense RNA interference approach to determine antibiotic mode of action. Antisense isogenic strains expressing antisense RNA to fabI were created using a tetracycline-regulated vector in Staphylococcus aureus. We demonstrated that down-regulation of FabI expression by induction of fabI antisense RNA induces a conditional lethal phenotype. In contrast, partial down-regulation gives a viable cell with a significant increase in sensitivity to FabI-specific inhibitors (i.e., a sensitized phenotype). More importantly, the mode of action for novel FabI inhibitors has been confirmed using this genetic approach in whole cell assay. These results indicate that controlled antisense technology provides a robust tool for defining and tracking the mode of action of novel antibacterial agents.  相似文献   

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