Antisense activity

Mery J., Brugidou Rabie A. A peptide nucleic acid (PNA) is more rapidly internalized in cultured neurons when coupled to a retro-inverso delivery peptide. The antisense activity depresses the target mRNA and protein in magnocellu-lar oxytocin neurons. Nucleic Acids Res. 

Thierry, A.R., Dritschilo, A. (1992). Intracellular availability of unmodified, phos-phorothioated and liposomally encapsulated oligodeoxynucleotides for antisense activity. Nucleic Acids Res., 20, 5691-5698. 

Lima, W.F., Brown-Driver, V., Fox, M., Hanecak, R. and Bruice, T. (1997) Combinatorial screening and rational optimization for hybridisation to folded Hepatitis C virus RNA of oligonucleotides with biological antisense activity J. Biol. Chem., 272, 626-638. 

Pisetsky, D.S. and Reich, C.F. (1994) Stimulation of murine lymphocyte proliferation by a phosphorothioate oligonucleotide with antisense activity for herpes simplex virus. Life Sci., 54, 101-107. 

Single-Stranded Oligonucleotides Used for Antisense Activity 540... 

For ASOs injected or infused directly into the CNS, the situation is quite different Neurons are known to take up PS ODNs, and antisense activity in CNS can be shown after local injections or intraventricular infusions. For PS ODNs that are administered locally to the CNS, safety pharmacology studies should be performed. For systemically administered PS ODNs, the scientific rationale is weak. 

Studies with PNA analogs have shown that these analogs can inhibit translation in cell-free systems, but to date no data have been reported from cellular studies (114,115). For morpholino oligomers, antisense activity has been reported in both cell-free and cellular assays (116, 117). Numerous oligonucleotides... 

In conclusion, phosphorothioate oligonucleotides may interact with a wide range of proteins through several types of mechanisms. These interactions may influence the pharmacokinetic, pharmacologic, and toxicologic properties of these molecules. They may also complicate studies on the mechanism of action of these drugs, and may obscure an antisense activity. For example, phosphorothio-... 

With respect to stereochemistry, substitution of one unbonded oxygen atom of the proch-iral phosphorus linkage in an oligonucleotide by sulfur, nitrogen or borane creates a chiral center leading to diastereomeric mixtures of RP and SP compounds in synthesis. Since the number of diastereomers increases by 2", this sums up to the formation of about half a million diastereomeric compounds during the synthesis of a 20-mer. Nevertheless, antisense activity remains intact in such diastereomeric mixtures. 

The use of methylphosphonates (12) as antisense compounds has been reviewed by several authors [83,84]. Very good nuclease resistance and a different mechanism of membrane penetration are the most remarkable features of this ODN modification [85]. The lack of anionic charge however renders the compounds relatively insoluble in water. Drug/target duplexes do not activate RNase-H. Therefore, high concentrations of up to 100 pM are required to achieve antisense activity. Nevertheless, methylphosphonates seem to be suited elements of chimeric oligonucleotides. 

Flanagan, W., et al.. Cellular penetration and antisense activity by a phenoxazine-substituted heptanucleotide. Nature Biotechnology, 1999, 17, 48-52. 

S. Sundaram, L. K. Lee and C. M. Roth, Interplay of polyethylenei-mine molecular weight and oligonucleotide backbone chemistry in the dynamics of antisense activity. Nucleic Acids Res., 35, 4396-4408... 

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