title: Antisense drug discovery and development.
abstract: Numerous chemically modified oligonucleotides have been developed so far and show their own unique chemical properties and pharmacodynamic/pharmacokinetic characteristics. Among all non-natural nucleotides, to the best of our knowledge, only five chemistries are currently being tested in clinical trials: phosphorothioate, 2´-O-methyl RNA, 2´-O-methoxyethyl RNA, 2´,4´-bridged nucleic acid/locked nucleic acid and the phosphorodiamidate morpholino oligomer. Since phosphorothioate modification can improve the pharmacokinetics of oligonucleotides, this modification is currently used in combination with all other modifications except phosphorodiamidate morpholino oligomer. For the treatment of metabolic, cardiovascular, cancer and other systemic diseases, the phosphorothioate class of drugs is obviously helpful, while superior efficacies can be observed in phosphorodiamidate morpholino oligomer compared to other classes of oligonucleotides for the treatment of Duchenne muscular dystrophy. Which properties of antisense molecules are actually essential for clinical applications? In this article, we provide an overview of the medicinal chemistry of existing non-natural antisense molecules, as well as their clinical applications, to discuss which properties of antisense oligonuculeotides affect therapeutic potency.
authors: Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors: Tsuyoshi
authors: T
authors: Yamamoto
authors: Moeka
authors: M
authors: Nakatani
authors: Keisuke
authors: K
authors: Narukawa
authors: Satoshi
authors: S
authors: Obika
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016373:DNA, Antisense / Q000737:chemistry; D055808:Drug Discovery / Q000379:methods*; D016189:Dystrophin / Q000235:genetics; D006801:Humans; D009025:Morpholines / Q000737:chemistry / Q000627:therapeutic use; D060172:Morpholinos; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides / Q000737:chemistry / Q000627:therapeutic use; D012313:RNA / Q000737:chemistry; D013873:Thionucleotides / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D001952:Bridged-Ring Compounds; D016373:DNA, Antisense; D016189:Dystrophin; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D013873:Thionucleotides; D012313:RNA; C091346:fomivirsen