Ribose-modified nucleic acids

Figure 5-3 Ribose-modified nucleic acids. B designates a nucleobase.

Conrad, F., Hanne, A., Gaur, R.K. and Krupp, G. (1995). Enzymatic synthesis of 2 -modified nucleic acids identification of important phosphate and ribose moieties in RNase P substrates. Nucleic Acids Res. 23, 1845-1853. 

Oligonucleotides with modified sugar components are another alternative to PNAs work in this direction was begun by Albert Eschenmoser, a famous synthetic chemist who was interested in the question as to why nature chose certain biomolecules for the processes of life and not others (Eschenmoser, 1991). This group carried out studies on the sugar components of the nucleic acids, in order to find out why D-ribose was used rather than another sugar. 

Nucleic acid degradation in humans and many other animals leads to production of uric acid, which is then excreted. The process initially involves purine nucleotides, adenosine and guanosine, which are combinations of adenine or guanine with ribose (see Section 14.1). The purine bases are subsequently modified as shown. 

Anyhow, a combination of the Scatchard technique and Raman spectroscopy shows (i) that SOAz actually interacts with DNA at the level of ribose backbones and (ii) that this kind of interaction does not drastically modify the DNA secondary structure, ethidium bromide encountering no more difficulty to intercalate between DNA plates SOAz being grafted or not on the nucleic acid. Thus, the behaviour of MYKO 63 and of SOAz appears quite different with respect to their mode of interaction with DNA despite their close chemical and molecular structure. This surprising observation may be of interest for understanding why SOAz does not induce any cumulative toxicity in vivo in contrast with MYKO 63. 

Despite the current problems concerning RNA at the origin of life—in particular, the origin of the first RNA molecules and enzyme-free replication—the idea of an RNA world turned out to be a very useful concept. It initiated the search for molecular templates and created an entirely new field which may be characterized as template chemistry (Orgel, 1992). A series of systematic studies were performed, for example, on the properties of nucleic acids with modified sugar moieties (Eschenmoser, 1993). This studies revealed the special role of ribose and... 

Figure 14.1. The biochemistry of nucleic acid. DNA and RNA are linear polymers in which each building block is a nucleotide. Nucleotides make up a ribose-phosphate scaffold, to which a base is joined. Four bases are used in both DNA and RNA adenine, cytosine, guanine, and thymine (used in DNA, modified from the chemically similar uracil used in RNA).

An alternative to the mirror image-approach is the direct selection of an aptamer from libraries of chemically modified RNAs. Many modifications in the ribose moiety of nucleic acids have been shown to dramatically increase their nuclease resistance. Modifications have to be chosen so as to be compatible with nucleic acid replicating enzymes such as reverse transcriptase, or DNA- and RNA-polymerases. The modifications most commonly used are those in which the 2 -OH group of pyrimidines is substituted by a 2 -fluoro-, or a 2 -amino group (1) [64,65],... 

Padilla, R., and Sousa, R. (1999) Efficient synthesis of nucleic acids heavily modified with non-canonical ribose 2 -groups using a mutant T7 RNA polymerase (RNAP). Nucleic Acids Res. 27, 1561-1563... 

Locked nucleic acids (LNA) are a modified RNA in which the ribose moiety is modified with an extra bridge connecting the 2 -0 and 4 -C atoms. Thus LNA nucleosides can be regarded as sugar-modified nucleosides. Madsen et al. synthesized the 2 -amino-LNA phosphoramidites... 

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