UTILITY OF CARBOCYCLIC NUCLEOSIDES FOR ANTISENSE THERAPY

与RNA结合亲和力增强的反义寡核苷酸 将使用碳环核苷修饰来开发靶标。 天然修饰核苷假尿苷(Psi)将被投资于 脱氧核糖核酸和2‘-甲基核糖核苷酸在 Gapmer硫代反义寡核苷酸。化学物质 亚磷酰胺的制备将遵循文献先例。 Psi靶向C-RAF激酶信息的Gapmer寡核苷酸 作为脱氧残基，将与具有2‘-O-的齐聚物一起制备。 机翼中含有甲基苯丙氨酸。寡核苷酸与RNA的亲和力 将测量目标，以及他们支持RNaseH的能力 中介卵裂。修饰和控制的寡核苷酸将是 整合到细胞系统中，并获得了生物学优势 PSI的合并将被确定。 建议的商业应用：反义的商业化 针对许多潜在靶向疾病的治疗受到以下限制 当前一代化合物的不良特性。 确定可增强亲和力或改进的修改 生物物理特性将通过更短的时间来降低成本 体内特异性较高的序列。

Antisense oligonucleotides with increased binding affinity for RNA targets will be developed using carbocyclic nucleoside modifications. The natural modified nucleoside pseudouridine (psi) will be invested in the context of a deoxyribonucleotide and a 2'- methyl ribonucleotide in gapmer phosphorothioate antisense oligonucleotides. The chemical preparation of phosphoramidites will follow literature precedent. Gapmer oligonucleotides targeted against C-raf kinase message with psi as a deoxy residue will be prepared, along with oligomers having 2'-O- methyl psi in the wings. The affinity of oligonucleotides for RNA targeted will be measured, along with their ability to support RNAse H- mediated cleavage. Modified and control oligonucleotides will be incorporated into cell systems, and the biological advantage gained from incorporation of psi will be determined. PROPOSED COMMERCIAL APPLICATION: Commercialization of antisense therapeutics against many potential target diseases is limited by undesirable properties of the current generation of compounds. Identification of modifications which enhance affinity, or improve biophysical properties would provide cost reduction via shorter sequences of higher specificity in vivo.