Nucleic Acids as Drugs and Drug Design Targets

4 NUCLEIC ACIDS AS DRUGS AND DRUG DESIGN TARGETS 

Nucleic-acid-related molecules (nucleotides, nucleosides, purines, pyrimidines) may also be used as dmgs themselves (and not only as dmg receptors). Once again, as discussed in chapters 7 and 9, this is most relevant in the areas of cancer and infectious disease, with purine/pyrimidine analogs being exploited as antimetabolites. 5-Fluorouracil is a well-described antineoplastic agent. Analogously, 5-fluorocytosine is used as an antifungal 

There are other ways in which nucleic-acid-related compounds could be exploited as therapeutics. A new, emerging area concerns the application of RNA as a dmg. The discovery of catalytic RNA (ribozymes) by Cech and Altman was a fundamental advance in nucleic acid chemistry. According to traditional double helix dogma, RNA was a passive information-transmitting molecule. The identification of ribozymes enabled the conceptual advance that RNA can also act as a catalyst for the following biochemical processes  

Ribozymes therefore show promise as therapeutic agents with which to downregulate RNA activity. For instance, a ribozyme-based drug could be used to attack the mRNA coding for a protein associated with a particular disease this attack would prevent the protein s expression by rendering the mRNA untranslatable. 

There are many examples of each of these possibilities (see figure 8.8). In the case of the 2 sugar position, most of the 2 -substititutions have been achieved with 2 -0-alkyl, 2 -amino, and 2 -fluoro replacements. Purine base substitutions have been performed with 2-aminopurine, xanthosine, and isoguanosine. Phosphodiester replacements have been effected using phosphorothioate substitutions. As for the non-nucleotide linkers, propanediol linkers have been employed. Using these various bioisosteric substitutions, 

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