2'-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation.
The 2'-position of the carbohydrate moiety has proven to be a fertile position for oligonucleotide modifications for antisense technology. The 2'-modifications exhibit high binding affinity to target RNA, enhanced chemical stability and nuclease resistance and increased lipophilicity. All high binding affinity 2'-modifications have C3'-endo sugar pucker. In addition to gauche effects, charge effects are also important in determining the level of their nuclease resistance. Pharmacokinetic properties of oligonucleotides are altered by 2'-conjugates. For certain modifications (e.g., 2'-F), the configuration at the 2'-position, arabino vs. ribo, determines their ability to activate the enzyme RNase H.
Manoharan
M
M
Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, CA 92008, USA. mmanohar@isisph.com
D017398:Alternative Splicing / Q000187:drug effects; D000588:Amines / Q000737:chemistry; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D016914:Ribonuclease H / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry
D000588:Amines; D002241:Carbohydrates; D003432:Cross-Linking Reagents; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D016914:Ribonuclease H