In recent years, nucleic acid aptamers, as with other functional nucleic acids such as siRNAs, have received attention as novel active ingredients for pharmaceutical drugs or diagnostic drugs in place of low-molecular-weight compounds and are under research and development in various ways around the world with the aim of medically applying the aptamers.
These nucleic acid aptamers are functional nucleic acids capable of strongly and specifically binding, through their own conformations, to target substances such as proteins to inhibit or suppress the functions of the target substances. A vascular endothelial growth factor (VEGF)-targeting modified RNA aptamer for treatment of age-related macular degeneration (Macugen) approved by FDA in 2004 is known as a typical example of the nucleic acid aptamer pharmaceutically used.
Such nucleic acid aptamers are constituted by only 4 kinds of bases in comparison with antibodies which are proteins composed of 20 kinds of amino acids. In addition, these 4 kines of bases are very similar in chemical or physical properties. For these reasons, the nucleic acid aptamers are disadvantageously limited by variations and performance.
In order to solve this problem, previously reported methods employ one or two types of modified natural bases composed of natural bases bound with substituents via linkers in a nucleic acid library for nucleic acid aptamer separation (Patent Literatures 1 and 2 and Non Patent Literatures 1 to 3). DNA aptamers that are intended for application to nucleic acid chips capable of detecting proteins and may be used in the diagnostic field are also known as modified nucleic acid aptamers comprising such modified natural bases (Non Patent Literature 3). However, one or two types of modified natural bases introduced in the modified nucleic acid aptamers result in the replacement of approximately 25% or more of bases in the whole nucleic acid aptamer with the modified natural bases. This raises another issue of reduced selectivity or cytotoxicity of the aptamers, though enhancing the production efficiency of the aptamers. Hence, use of the modified nucleic acid aptamers having the modified natural bases is currently limited to diagnosis, and none of such aptamers have been approved as therapeutic drugs (Non Patent Literature 3).
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