Antisense drugs mechanisms

Crooke, S.T. (1999) Molecular mechanisms of action of antisense drugs. Antisense Biochim. Biophys. Acta., 1489, 31 14. 

Vollmer J, Krieg A. Mechanisms and therapeutic applications of immune modulatory oligodeoxynucleotide and oligoribonucleotide ligands for toll-like receptors. In Crooke ST, ed., Antisense Drug Technology, Boca Raton Taylor Francis 2007 747-772. 

Crooke ST. Molecular mechanisms of antisense drugs RNase H. Antisense Nucleic Acid Drug Dev 1 998 8 1 33-134. 

Manoharan M (2002) Oligonucleotide conjugates as potential antisense drugs with improved uptake, biodistribution, targeted delivery, and mechanism of action. Antisense Nucleic Acid Drug Dev 12 103-128... 

Lima W, Wu H, Crooke ST (2008) The RNase H mechanism. In Crooke ST (ed) Antisense drug technology principles, strategies, and applications, 2nd edn. CRC, Boca Raton, pp 47-74... 

What are the mechanisms of action of antisense and RNA interference drugs in the treatment of diseases ... 

Fomivirsen (Vitravene), an anti-CMV agent, is the first antisense oligonucleotide to be approved by the U. S. Food and Drug Administration (FDA) as an antiviral therapy. Fomivirsen is an oligonucleotide complementary to the major immediate early region 2 (IE2) of CMV mRNA. By binding to IE2 mRNA, fomivirsen prevents its translation to protein and thereby blocks viral replication. Because this mechanism of action is... 

Mechanism of Action. Fomivirsen has a unique mechanism of antiviral action. This drug contains an amino acid sequence that is opposite or complimentary to the messenger RNA sequence controlling CMV replication. Because of this opposing or antisense sequence, fomivirsen inhibits several aspects of CMV replication, and also inhibits the viruses ability to adsorb to the surface of host cells. 

Novel antisense anti-MDM2 mixed-backbone oligonucleotides Proof of principle, in vitro and in vivo activities, and mechanisms. Curr. Cancer Drug Targets 5 43-49. 

The process of transcription can also occur in reverse, from RNA to DNA, when the sequence coded in RNA is transcribed into antisense DNA by reverse transcriptase enzymes first discovered by Temin and Mizutani [18] and Baltimore [19]. Further integrase enzymes insert the DNA sequence into the native DNA. This is the mechanism by which viruses infect their host organisms and can be stopped by antiviral drugs, such as azidothymine (AZT) that inhibits F1IV reverse transcriptase. Other processes such as the extension of telomeres at the ends of chromosomes by telomerase, to control programmed cell death, use the same mechanism. 

There are other complex issues with regard to the assessment of safety pharmacology studies. With the oligonucleotide therapeutics that modulate the translation of mRNA to proteins, like antisense/siRNA, there is a lag between administration of the drug and the pharmacologic activity that is mediated by reduction in protein levels. This lag is related to the mechanism of action and how long it takes for a reduction in protein synthesis to be reflected in reduced protein levels. Because of this lag it is probably better to... 

For drug screening purposes, the titratable repression of the Tet promoter by addition of tetracycline allows control over the cellular concentration of a specific target protein. Similar to antisense RNA-based cell sensitization described in Section 7.2.2.1, this approach provides a MOA (mechanism of action)-based assay because cells with reduced target protein levels become hypersensitive... 

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