Warfield Kelly L, Panchal Rekha G, Aman M Javad, Bavari Sina
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.
Curr Opin Mol Ther. 2006 Apr;8(2):93-103.
Antisense oligomers (ASOs) represent a promising technology to treat viral and bacterial infections, and have already been shown to be successful against a variety of pathogens in cell culture studies and nonhuman primate models of infection. For these reasons, antisense technologies are being pursued as treatments against biothreat agents such as Ebola virus, dengue virus and Bacillus anthracis. Several generations of modified oligonucleotides have been developed to maximize nuclease resistance, target affinity, potency, cell entry, and other pharmacokinetic properties. First-generation ASOs contain phosphorothioate modifications to increase stability through nuclease resistance. Further chemical modifications in second-generation ASOs include 2'-O-methyl and 2'-O-methoxy-ethyl oligos, which increase nuclease resistance and oligo:RNA binding affinities. Third-generation ASOs contain a variety of chemical modifications that enhance stability, affinity and bioavailability. A fourth class of oligonucleotide-based compounds consists of small interfering RNAs, which have recently become widely used for gene knockdown in vitro and in vivo. This review focuses on the third-generation phosphorodiamidate morpholino oligomers, which are nonionic and contain a morpholine ring instead of a ribose, as well as phosphorodiamidate linkages in place of phosphorothioates. Multiple antisense oligomer-based therapeutics are being developed for use against biothreat agents, and antisense drugs will likely become a critical member of our arsenal in the defense against highly pathogenic, emerging or genetically engineered pathogens.
反义寡聚核苷酸（ASOs）是一种治疗病毒和细菌感染的很有前景的技术，并且在细胞培养研究和非人类灵长类动物感染模型中已被证明对多种病原体有效。基于这些原因，反义技术正被作为针对埃博拉病毒、登革热病毒和炭疽杆菌等生物威胁因子的治疗方法来研究。已经开发了几代修饰寡核苷酸，以最大限度地提高核酸酶抗性、靶标亲和力、效力、细胞摄取及其他药代动力学特性。第一代ASOs含有硫代磷酸酯修饰，以通过核酸酶抗性提高稳定性。第二代ASOs的进一步化学修饰包括2'-O-甲基和2'-O-甲氧基乙基寡核苷酸，它们提高了核酸酶抗性和寡核苷酸与RNA的结合亲和力。第三代ASOs含有多种化学修饰，可增强稳定性、亲和力和生物利用度。第四类基于寡核苷酸的化合物由小干扰RNA组成，它们最近已广泛用于体外和体内的基因敲低。本综述重点关注第三代吗啉代二氨基磷酸酯寡聚物，它们是非离子型的，含有吗啉环而非核糖，并且用二氨基磷酸酯键取代了硫代磷酸酯键。多种基于反义寡聚物的疗法正在开发中，用于对抗生物威胁因子，反义药物很可能会成为我们抵御高致病性、新出现的或基因工程病原体武器库中的关键一员。
