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Antisense Oligonucleotides

Phosphorothioate
The driving force for the search for novel chemical modification groups compatible with Watson-Crick hybridization of oligonucleotide was based on the observation of the short stability of naturally occurring oligonucleotides with phosphodiester bonds. Oligonucleotides with natural phosphodiester bonds are highly susceptible to rapid degradation by cellular nucleases. Cellular nucleases have endonuclease activity as well such that 3 and 5 end caps are not sufficient to prevent from degradation.

Modification of the phosphodiester bond by replacing one of the non-bridging oxygen by sulfur imparts resistance to nuclease degradation, but in general hybridize to the target sequences with lesser affinity than the phosphodiester counter part. This can be minimized by the use of LNA and 2-5 linked oligos as described in the section below. The sulfur-substituted oligonucleotides have a phosphorothioate linkage and are termed as phosphorothioates or simply as S-oligo. Phosphorothioate oligos are synthesized by Gene Link using the Beaucage (4) sulfurizing reagent. The sulfurization reaction is rapid and is performed on automated DNA synthesizers yielding greater than 96% phosphorothioate linkages; the remainder are phosphodiester linkages. Custom phosphorothioate oligonucleotides synthesized by Gene Link can be specified to have all the diester bonds substituted or only some selected diester linkages depending upon the researchers experimental requirement. Substitution of all diester linkage is recommended to provide greater nuclease resistance.

Internucleotide Linkages
Natural diester linkage, Thioate (S-Oligo) linkage & DNA, RNA and 2'O methyl base

Propyne* Analogs
It has been shown that C-5 propyne analogs of dC and dT when substituted in phosphorothioate oligonucleotide imparts greater inhibition of gene expression due to increased binding affinity to the target mRNA and increased stability (5). Based on the above information antisense oligonucleotide could either be Phosphorothioated at all diester linkages or combined with substitutions of dC and dT by C-5 propyne analogs pdC and pdU.

The use of propyne analogs is covered by patents and licensing agreements. The sale of propyne-modified oligos is for research use only. See license agreement below*.

C5 Propyne Analogs
C5 propyne analogs of dC and dT

*Propyne Analog Use Agreement
Our agreement with Glen Research who in turn has an agreement with Isis Pharmaceuticals, Inc. allows us to sell to you C-5 Propynes and G-clamps that are ultimately used for RESEARCH PURPOSES ONLY. In accordance with this agreement, we must inform you of the uses to which these products may be put, which are described below. This product is covered by patents or patents pending owned by Isis Pharmaceuticals, Inc. (Isis). Purchase of this product includes a limited license to use this product solely for internal research. This license specifically excludes (and you have no right to use this product for): (a) therapeutic or diagnostic applications (including products or services that incorporate this product), (b) any in vivo toxicity/safety study in support of an investigational new drug application (or foreign counterpart), (c) resale (including sale of any products or services that incorporate this product) or (d) gene functionalization activities (including products or services that incorporate data derived from gene functionalization activities) if such activities have commercial application, any and all of which require a separate license from Isis. Neither this product nor any product created through its use may be used in human clinical trials. In the event you have a separate agreement with Isis regarding this product, which explicitly states that the foregoing is not applicable to you, your use of this product will be governed by the terms of such agreement. In no event does the limited license included with the purchase of this product expand or alter the scope of the license granted pursuant to such agreement.

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