UTILITY OF CARBOCYCLIC NUCLEOSIDES FOR ANTISENSE THERAPY

具有增加的RNA结合亲和力的反义寡核苷酸 将使用碳环核苷修饰来开发靶点。 天然修饰的核苷类假尿苷（psi）将投资于 脱氧核糖核苷酸和2 '-甲基核糖核苷酸的上下文在 gapmer硫代磷酸酯反义寡核苷酸。 化学 亚磷酰胺的制备将遵循文献先例。 用psi靶向C-raf激酶信使的Gapmer寡核苷酸 作为脱氧残基，沿着制备具有2 ′-O- 机翼上的甲基PSI 寡核苷酸对RNA的亲和力 将测量靶向的RNA酶，沿着它们支持RNA酶H-的能力。 介导的裂解。 修饰的寡核苷酸和对照寡核苷酸将被 整合到细胞系统中， 将确定来自psi的结合。 拟定的商业应用：反义核酸的商业化 针对许多潜在目标疾病的治疗受到以下因素的限制 这是当前一代化合物的不期望的性质。 鉴定增强亲和力或改善亲和力的修饰 生物物理性质将通过更短的时间提供成本降低。 体内特异性更高的序列。

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.