SYNTHETIC OLIGONUCLEOTIDES FOR TRYPANOSOME CHEMOTHERAPY

与吖啶偶联的反义磷二酸酯寡核苷酸，以及 反义甲基膦酸寡核苷酸对培养锥虫的杀伤作用 Brucei在第一阶段计划中。在第二阶段计划中，反义 寡核苷酸将在碱基、糖和磷酸二酯上被培养 功能基团，以提高其治疗效力。这些 修改将被设计为增加寡核苷酸细胞 对靶RNA或DNA的穿透性、稳定性和功能抑制。 核酸靶标将扩大到39个核苷酸的拼接范围之外 锥虫mRNAs的前导序列，包括小的核RNA， 几种mRNA序列的编码和非编码，以及肌动蛋白基因 启动子区域。然后将对修饰的寡核苷酸进行检测 培养中的锥虫原环状和增强型 对血流形式的治疗作用。主动型 寡核苷酸将被用来测试治疗效果 锥虫感染小鼠。积极的结果将使 医药行业发展的新反义 锥虫等的寡核苷酸化疗药物 寄生虫。

Antisense phosphodiester oligonucleotides, conjugated with acridine, and antisense methylphosphonate oligonucleotides, killed cultured Trypanosome brucei in the Phase I program. In the Phase II program, antisense olignucleotides will be edified at the base, sugar, and phosphodiester functional groups to increase their therapeutic potency. These modifications will be designed to increase oligonucleotide cell penetration, stability, and functional inhibition of target RNA or DNA. The nucleic acid target will be expanded beyond the 39 nucleotide spliced leader sequence of trypanosome mRNAs to include the small nuclear RNAs, the coding and non-coding of several mRNA sequences, and the actin gene promoter region. Modified oligonucleotides then will be tested against the trypanosome procyclic form in culture, and those with enhanced therapeutic activity against the bloodstream form. Active oligonucleotides will be tested for therapeutic efficacy using trypanosome infected mice. Positive results will be of interest to the pharmaceutical industry for the development of new antisense oligonucleotide chemotherapeutic agents for trypanosomes and other parasites.