Crooke S T
Isis Pharmaceuticals, Carlsbad, California 92008.
FASEB J. 1993 Apr 1;7(6):533-9. doi: 10.1096/fasebj.7.6.7682523.
Although many issues remain to be resolved, recent progress suggests that oligonucleotides may have therapeutic potential. The first therapeutic oligonucleotide, ISIS 2105, an oligonucleotide designed to treat genital warts, has completed Phase I clinical trials and is undergoing Phase II testing. Conceptually, oligonucleotides may interact with nucleic acid or nonnucleic acid receptors; however, rational design of oligonucleotide drugs to interact with nucleic acid receptors is significantly simpler because the factors that determine affinity and selectivity are better understood. Recent progress demonstrates that this information can be coupled to rapid advances in the medicinal chemistry of oligonucleotides to create new generations of oligonucleotide drugs with dramatically improved properties. The purposes of this review are to place oligonucleotide therapeutics in the context of modern molecular drug discovery and to summarize progress in understanding the pharmacodynamic properties of oligonucleotides designed to bind to nucleic acid receptors. The pharmacokinetic and toxicologic properties of oligonucleotides have been reviewed recently (1-4). The activities of oligonucleotides that bind to nonnucleic acid receptors will be considered in future reviews.
尽管仍有许多问题有待解决，但最近的进展表明，寡核苷酸可能具有治疗潜力。首个治疗性寡核苷酸ISIS 2105，一种用于治疗尖锐湿疣的寡核苷酸，已完成I期临床试验，正在进行II期测试。从概念上讲，寡核苷酸可能与核酸或非核酸受体相互作用；然而，设计与核酸受体相互作用的寡核苷酸药物在理论上要简单得多，因为决定亲和力和选择性的因素已得到更好的理解。最近的进展表明，这些信息可以与寡核苷酸药物化学的快速发展相结合，以创造出性能大幅改善的新一代寡核苷酸药物。本综述的目的是将寡核苷酸治疗置于现代分子药物发现的背景下，并总结在理解与核酸受体结合的寡核苷酸的药效学特性方面取得的进展。寡核苷酸的药代动力学和毒理学特性最近已有综述（1-4）。与非核酸受体结合的寡核苷酸的活性将在未来的综述中讨论。
