title: Potent and selective inhibition of gene expression by an antisense heptanucleotide.
abstract: Factors that govern the specificity of an antisense oligonucleotide (ON) for its target RNA include accessibility of the targeted RNA to ON binding, stability of ON/RNA complexes in cells, and susceptibility of the ON/RNA complex to RNase H cleavage. ON specificity is generally proposed to be dependent on its length. To date, virtually all previous antisense experiments have used 12-25 nt-long ONs. We explored the antisense activity and specificity of short (7 and 8 nt) ONs modified with C-5 propyne pyrimidines and phosphorothioate internucleotide linkages. Gene-selective, mismatch sensitive, and RNase H-dependent inhibition was observed for a heptanucleotide ON. We demonstrated that the flanking sequences of the target RNA are a major determinant of specificity. The use of shorter ONs as antisense agents has the distinct advantage of simplified synthesis. These results may lead to a general, cost-effective solution to the development of antisense ONs as therapeutic agents.
authors.affiliation: Gilead Sciences, Foster City, CA 94404, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Wagner
authors.forename: M D
authors.initials: MD
authors.lastname: Matteucci
authors.forename: D
authors.initials: D
authors.lastname: Grant
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.forename: B C
authors.initials: BC
authors.lastname: Froehler
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D003362:Cost-Benefit Analysis; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009690:Nucleic Acid Conformation; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D016914:Ribonuclease H / Q000378:metabolism
chemical_list: D016376:Oligonucleotides, Antisense; D012313:RNA; D016914:Ribonuclease H