title: Triple-strand-forming methylphosphonate oligodeoxynucleotides targeted to mRNA efficiently block protein synthesis.
abstract: Antisense oligonucleotides are ordinarily targeted to mRNA by double-stranded (Watson-Crick) base recognition but are seldom targeted by triple-stranded recognition. We report that certain all-purine methylphosphonate oligodeoxyribonucleotides (MPOs) form stable triple-stranded complexes with complementary (all-pyrimidine) RNA targets. Modified chloramphenicol acetyltransferase mRNA targets were prepared with complementary all-pyrimidine inserts (18-20 bp) located immediately 3' of the initiation codon. These modified chloramphenicol acetyltransferase mRNAs were used together with internal control (nontarget) mRNAs in a cell-free translation-arrest assay. Our data show that triple-strand-forming MPOs specifically inhibit protein synthesis in a concentration-dependent manner (> 90% at 1 microM). In addition, these MPOs specifically block reverse transcription in the region of their complementary polypyrimidine target sites.
authors.affiliation: Genta, Inc., San Diego, CA 92121.
authors.forename: M A
authors.initials: MA
authors.lastname: Reynolds
authors.forename: L J
authors.initials: LJ
authors.lastname: Arnold
authors.forename: M T
authors.initials: MT
authors.lastname: Almazan
authors.forename: T A
authors.initials: TA
authors.lastname: Beck
authors.forename: R I
authors.initials: RI
authors.lastname: Hogrefe
authors.forename: M D
authors.initials: MD
authors.lastname: Metzler
authors.forename: S R
authors.initials: SR
authors.lastname: Stoughton
authors.forename: B Y
authors.initials: BY
authors.lastname: Tseng
authors.forename: T L
authors.initials: TL
authors.lastname: Trapane
authors.forename: P O
authors.initials: PO
authors.lastname: Ts'o
mesh_terms: D001483:Base Sequence; D002474:Cell-Free System; D017931:DNA Primers / Q000737:chemistry; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D063065:Organophosphonates; D014176:Protein Biosynthesis; D011687:Purines / Q000737:chemistry; D012333:RNA, Messenger / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D017931:DNA Primers; D009838:Oligodeoxyribonucleotides; D063065:Organophosphonates; D011687:Purines; D012333:RNA, Messenger; D018894:Reverse Transcriptase Inhibitors