There is much interest in the medical uses of nucleic acids. For example, antisense, ribozymes, aptamer and RNA interference (RNAi) technologies are all being developed for potential therapeutic applications. The design of nucleic acids, particularly oligonucleotides, for in vivo delivery requires consideration of various factors including binding strength, target specificity, serum stability, resistance to nucleases and cellular uptake. A number of approaches have been proposed in order to produce oligonucleotides that have characteristics suitable for in vivo use, such as modified backbone chemistry, formulation in delivery vehicles and conjugation to various other moieties. Therapeutic oligonucleotides with characteristics suitable for systemic delivery would be particularly beneficial.
There are many oligonucleotides with modified chemical backbones, like peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methylphosphonates, phosphoramidates and thiophosphoramidates. Each of these types of oligonucleotides has reported advantages and disadvantages. For example, peptide nucleic acids (PNAs) display good nuclease resistance and binding strength, but have reduced cellular uptake in test cultures; phosphorothioates display good nuclease resistance and solubility, but are typically synthesized as P-chiral mixtures and display several sequence- non-specific biological effects; methylphosphonates display good nuclease resistance and cellular uptake, but are also typically synthesized as P-chiral mixtures and have reduced duplex stability.
The N3'-P5'phosphoramidate internucleoside linkages are reported to display favorable binding properties, nuclease resistance, and solubility (I did work for quite some time in this field and I had opportunity to interact with Dr. Sergei Gryaznov and group). Though this field is getting wider and wider with many companies trying with some innovative ideas, the real concern in this field is that the polyanionic nature of oligonucleotides reduces the ability of the compound to cross lipid membranes, limiting the efficiency of cellular uptake.But thanks to many other groups they are trying to concentrating on this issue and hope there will be may drugs in the days to come. There are many drugs already in the market by ISIS and Geron corporation has many patents to its credit in the many patents for its novel work (Dr.Sergei, Dr.Cristzina Pongracz and many others have lot of work in this field) N3'-P5'phosphoramidate internucleoside linkages. Though there were a few players in this field of nucleic acids(5-6 years' back), now a days when ever I read any medicinal chemistry news, I do find lot many companies contributing to this field of nucleic acids. Hope there will be many drugs from this field with reduced side effects....
There are many oligonucleotides with modified chemical backbones, like peptide nucleic acids (PNAs), locked nucleic acids (LNAs), methylphosphonates, phosphoramidates and thiophosphoramidates. Each of these types of oligonucleotides has reported advantages and disadvantages. For example, peptide nucleic acids (PNAs) display good nuclease resistance and binding strength, but have reduced cellular uptake in test cultures; phosphorothioates display good nuclease resistance and solubility, but are typically synthesized as P-chiral mixtures and display several sequence- non-specific biological effects; methylphosphonates display good nuclease resistance and cellular uptake, but are also typically synthesized as P-chiral mixtures and have reduced duplex stability.
The N3'-P5'phosphoramidate internucleoside linkages are reported to display favorable binding properties, nuclease resistance, and solubility (I did work for quite some time in this field and I had opportunity to interact with Dr. Sergei Gryaznov and group). Though this field is getting wider and wider with many companies trying with some innovative ideas, the real concern in this field is that the polyanionic nature of oligonucleotides reduces the ability of the compound to cross lipid membranes, limiting the efficiency of cellular uptake.But thanks to many other groups they are trying to concentrating on this issue and hope there will be may drugs in the days to come. There are many drugs already in the market by ISIS and Geron corporation has many patents to its credit in the many patents for its novel work (Dr.Sergei, Dr.Cristzina Pongracz and many others have lot of work in this field) N3'-P5'phosphoramidate internucleoside linkages. Though there were a few players in this field of nucleic acids(5-6 years' back), now a days when ever I read any medicinal chemistry news, I do find lot many companies contributing to this field of nucleic acids. Hope there will be many drugs from this field with reduced side effects....
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