Antisense agents

Antirachitic vitamin Antiredeposition agents Antirust additives Antiscaling additives Antiscorbutic vitamin Antiseize material Antisense agents Antisense DNA... 

Antisense agents are substances (in this case oligonucleotides) which are intended to prevent illnesses, for example by blocking certain mRNA sequences. 

RNAi technology has obvious therapeutic potential as an antisense agent, and initial therapeutic targets of RNAi include viral infection, neurological diseases and cancer therapy. The synthesis of dsRNA displaying the desired nucleotide sequence is straightforward. However, as in the case of additional nucleic-acid-based therapeutic approaches, major technical hurdles remain to be overcome before RNAi becomes a therapeutic reality. Naked unmodified siRNAs for example display a serum half-life of less than 1 min, due to serum nuclease degradation. Approaches to improve the RNAi pharmacokinetic profile include chemical modification of the nucleotide backbone, to render it nuclease resistant, and the use of viral or non-viral vectors, to achieve safe product delivery to cells. As such, the jury remains out in terms of the development and approval of RNAi-based medicines, in the short to medium term at least. 

Aptamers appear to display low immunogenicity but, when administered systemically, they are quickly excreted via size-mediated renal clearance. In order to prevent renal removal, such aptamers are usually conjugated to PEG. PEG may also help further protect the aptamers from degradation by serum nucleases native aptamers are prone to nuclease attack, but their half-lives can most effectively be extended via chemical modification, as discussed earlier in the context of antisense agents. 

Antiselective poisoning, 5 258 Antisense agents, 77 626-627 Antisense compounds, 77 13-14 Antisense mechanism, 77 627 Antisense oligonucleotides, 77 627, 628 Antiseptics, 3 605, 606... 

The torsion angles around the bonds of the sugar-phosphate DNA backbone are of decisive importance for the secondary structure of DNA as well as for base-base recognition. [44] For antisense agents to be effective inhibitors of protein expression in vivo, they have to resist the action of DNA-degrading enzymes and bind to their... 

Only one antisense-based product has been approved to date (in 1998) and, although several such antisense agents continue to be clinically evaluated, it is unlikely that a large number of... 

Antigene sequences and ribozymes form two additional classes of antisense agents. However, the therapeutic potential of these agents is only now beginning to be appraised. Certain RNA sequences can function as catalysts. These so-called ribozymes function to catalyse cleavage at specific sequences in a specific mRNA substrate. Many ribozymes will cleave their target mRNA where there exists a particular triplet nucleotide sequence G-U-C. Statistically, it is likely that this triplet will occur at least once in most mRNAs. 

Weiss, B. (1991) Antisense Oligodeoxynudeotides and Antisense Agents. Novel Pharmacological and Therapeutic Agents. CRC Press, Boca Raton, p. 252. 

The very specific activity of PMOs makes them inherently less toxic than other antisense agents. In addition, the neutral... 

Hudziak RM, Summerton J, Weller DD, Iversen PL, Antiproliferative effects of steric blocking phosphorodiamidate morpholino antisense agents directed against c-myc, Antisense Nucleic Acid Drug Dev 2000 10 163-176. 

Peptide nucleic acids (PNA) are novel antisense oligonucleotides (see Section 1.6.2) which contain a polypeptide backbone. Receptor-mediated transcytosis can be exploited to promote their delivery to the CNS. For example, the attachment of PNAs to the anti-transferrin (0X26) receptor antibodies has been shown to increase the brain uptake of the PNAs, without loss of the ability of the PNAs to hybridize to target mRNA. However, antisense agents will not exert pharmacologic effects in vivo following delivery to... 

As phosphorothioate oligonucleotides are widely used as antisense agents, there have been a number of reports on their mode of action. Using Rp and Sp phosphorothioate internucleotide linkages in ODNs, it was shown that Serratia marcescens endonuclease hydrolyses the Rp phosphorothioate bond with inversion of configuration at phosphorus. The presence of an Sp phosphorothioate... 

This insight has been extensively supported and extended by the results of the contemporary search in medicinal chemistry for structural nucleic-acid variants that may have the potential of acting as antisense agents (see, for example, Hyrup and Nielsen, 1996 Herdewijn, 1996 l.eumann, 2002). 

To create antisense inhibitors that clearly wak through non-RNase H meehanisms, the antisense agents must be modified sufficiently not to support RNase H cleavage. Fortunately, numerous analogs have been identified that do not support RNase H cleavage. These can be... 

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