Oligonucleotide conjugates as potential antisense drugs with improved uptake, biodistribution, targeted delivery, and mechanism of action.
This review summarizes the effect of conjugating small molecules and large biomacromolecules to antisense oligonucleotides to improve their therapeutic potential. In many cases, favorable changes in pharmacokinetic and pharmacodynamic properties were observed. Opportunities exist to change the terminating mechanism of antisense action or to enhance the RNase H mode of action via conjugate formation.
Manoharan
Muthiah
M
Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc, Carlsbad, CA 92008, USA. mmanoharan@isisph.com
D000818:Animals; D001693:Biological Transport, Active; D002241:Carbohydrates; D002412:Cations; D002784:Cholesterol; D003432:Cross-Linking Reagents; D004705:Endocytosis; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011092:Polyethylene Glycols; D011166:Porphyrins; D011485:Protein Binding; D016914:Ribonuclease H / Q000378:metabolism; D014018:Tissue Distribution
D002241:Carbohydrates; D002412:Cations; D003432:Cross-Linking Reagents; D008024:Ligands; D016376:Oligonucleotides, Antisense; D011166:Porphyrins; D011092:Polyethylene Glycols; D002784:Cholesterol; D016914:Ribonuclease H