SYNTHETIC OLIGONUCLEOTIDES FOR TRYPANOSOME CHEMOTHERAPY

与吖啶缀合的反义磷酸二酯寡核苷酸，和 反义甲基膦酸寡核苷酸，杀死培养的锥虫 在第一阶段计划中的布氏杆菌。在第二阶段计划中， 寡核苷酸将在碱基、糖和磷酸二酯上被修饰， 功能基团，以增加其治疗效力。这些 将设计修饰以增加寡核苷酸细胞 靶RNA或DNA的渗透、稳定性和功能抑制。 核酸靶将扩增超过39个核苷酸剪接的 锥虫mRNA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 启动子区然后将针对以下各项测试修饰的寡核苷酸： 培养中的锥虫原环形式，以及那些具有增强的 对血流形式的治疗活性。活性 将使用以下方法测试寡核苷酸的治疗功效： 锥虫感染的小鼠。积极的结果将是感兴趣的， 制药工业的发展新的反义 用于锥虫和其他的寡核苷酸化疗剂 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.